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Background: Advances in medical technology have resulted in changes to enteral tube feeding (ETF). Standard practice in the UK is to use commercial formula for ETF via the stomach or small intestine; however, blended diets are becoming increasingly popular. Emerging evidence shows benefits of a blended diet although evidence informing clinical guidance is sparse. Consequently, there is disparity in practice, and it remains unclear which patient groups may benefit most from a blended diet. Aim: To demonstrate the initiation of a blended diet in clinical practice. Methods: This case report features a 2-year-old child requiring ETF in the context of hypotonia, developmental delay and faltering growth. Results: In this instance, a blended diet resulted in improved gastrointestinal symptoms and adequate growth. Conclusion: This case demonstrates the successful implementation of a blended diet and associated benefits. Blended diets may benefit others requiring ETF and should be considered on an individualised basis.

Ethylmalonic encephalopathy is a rare autosomal recessive mitochondrial disorder caused by pathogenic biallelic variants in the ETHE1 gene. The phenotype of this disease has been attributed to deficiency in the mitochondrial sulfur dioxygenase leading to many downstream effects. Ethylmalonic encephalopathy classically presents with developmental regression, petechiae, acrocyanosis, and chronic diarrhea. The neurologic phenotype includes hypotonia, spastic diplegia, ataxia, and developmental delay. As more patients with this condition are described, the neurologic phenotype continues to expand. Although strokelike episodes or metabolic strokes have been studied in other mitochondrial disorders, they have not been thoroughly reported in this disorder. Herein, we describe 3 patients with ethylmalonic encephalopathy who presented clinically with strokelike episodes and strokelike abnormalities on brain magnetic resonance imaging in the setting of acute illness, and the long-term sequelae with evolution into cystic changes in one of these subjects.

Reversible infantile respiratory chain deficiency, previously termed reversible infantile cytochrome c oxidase (COX) deficiency myopathy, is a rare mitochondrial disorder that is characterized by severe hypotonia and generalized muscle weakness in infancy that is associated with lactic acidosis. Affected infants will spontaneously recover, if they survive the first months of life. Here, we present the case of a 4-week-old girl who initially presented with hyperammonemia, hypotonia, and failure to thrive, for which she was referred for genetic evaluation. After several tests, a distinct genetic syndrome could not be identified and she continued to deteriorate. A muscle biopsy was performed and demonstrated severe mitochondrial myopathy with abundant COX-negative fibers. Ultrastructural abnormalities of the mitochondria, diagnostic of mitochondrial myopathy, were identified on electron microscopy. Molecular studies revealed the classic homoplasmic disease causing mutation, m.14674 T>C in the MT-TE gene, associated with reversible COX deficiency. Although hyperammonemia is an unusual presentation for mitochondrial myopathies, specifically reversible infantile respiratory chain deficiency, it should be included in the list of possible presenting symptoms for this condition.

Congenital disorders of glycosylation (CDG) are multisystemic inherited metabolic disorders with marked phenotypic variability. The most frequent described type is PMM2-CDG (earlier known as CDG Type Ia) which presents either with pure neurologic features or with combined neurologic and systemic features. The classical presentation is characterized by varied combinations of developmental delay, hypotonia, ataxia, dysmorphism, inverted nipples, and abnormal fat distribution. Strokelike episodes and seizures are known acute complications that usually occur on a background of developmental delay, ataxia, or dysmorphism. We report here a developmentally normal young girl who presented with isolated strokelike episodes and was diagnosed to have CDG Type Ia. This condition should be kept in the differentials of unexplained strokelike episodes in children. The diagnosis has important therapeutic and prognostic implications.

Variants in CAMK2-associated genes have recently been implicated in neurodevelopmental disorders and intellectual disability. The clinical manifestations reported in patients with mutations in these genes include intellectual disability (ranging from mild to severe), global developmental delay, seizures, delayed speech, behavioral abnormalities, hypotonia, episodic ataxia, progressive cerebellar atrophy, visual impairments, and gastrointestinal issues. Phenotypic heterogeneity has been postulated. We present a child with neurodevelopmental disorder caused by a pathogenic CAMK2B variant inherited from a healthy mother. A more mildly affected sib was determined to have the same variant. Monoallelic mutations in CAMK2B in patients have previously only been reported as de novo mutations. This report adds to the clinical phenotypic spectrum of the disease and demonstrates intrafamilial variability of expression of a CAMK2B mutation.

Variants in PURA have recently been associated with an autosomal dominant form of PURA-related neurodevelopmental disorders. Using whole exome sequencing, patients with neurological phenotypes including hypotonia, developmental delay, learning disabilities, and seizures were identified to have de novo variants in PURA. We describe a proband with features similar to the previously described cases with PURA variants, but including additional features, such as short stature, delayed bone age, and delayed puberty. Exome sequencing revealed a novel pathogenic nonsense variant, c.190A>T (p.Lys64*; NM_005859), in PURA that was not inherited from the proband’s mother. In the recent literature, a significant number of patients with variants in PURA have been described, but to our knowledge, none of these patients have the delayed bone age and growth plateau observed in the proband. It is therefore possible that the above PURA variant may be responsible for the novel features and thus expands the PURA-related phenotype spectrum.

Prader–Willi syndrome is a genetic disorder that is characterized by obesity, characteristic facial features, hypotonia, and sleep apnea. These abnormalities mean that airway management is difficult in such patients. Several previous reports suggest that neuromuscular blocking agents should not be used to reduce airway and respiratory complications in these patients. However, this is not always possible. Here, we report the case of a patient with Prader–Willi syndrome in whom anesthesia for ophthalmic surgery was managed successfully using sugammadex after administration of rocuronium.

De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy With Contractures, Macrocephaly, and Dyskinesias Helbig KL, Lauerer RJ, Bahr JC, et al. Am J Hum Genet. 2019;104(3):562. Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders often beginning in infancy or early childhood that are characterized by intractable seizures, abundant epileptiform activity on electroencephalogram (EEG), and developmental impairment or regression. CACNA1E is highly expressed in the central nervous system and encodes the α1-subunit of the voltage-gated CaV2.3 channel, which conducts high-voltage-activated R-type calcium currents that initiate synaptic transmission. Using next-generation sequencing techniques, we identified de novo CACNA1E variants in 30 individuals with DEE, characterized by refractory infantile-onset seizures, severe hypotonia, and profound developmental impairment, often with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early death. Most of the 14, partially recurring, variants cluster within the cytoplasmic ends of all 4 S6 segments, which form the presumed CaV2.3 channel activation gate. Functional analysis of several S6 variants revealed consistent gain-of-function effects comprising facilitated voltage-dependent activation and slowed inactivation. Another variant located in the domain II S4-S5 linker results in facilitated activation and increased current density. Five participants achieved seizure freedom on the antiepileptic drug topiramate, which blocks R-type calcium channels. We establish pathogenic variants in CACNA1E as a cause of DEEs and suggest facilitated R-type calcium currents as a disease mechanism for human epilepsy and developmental disorders.

Pontine tegmental cap dysplasia (PTCD) is a rare condition that affects the brain stem and multiple cranial nerves, which can result in bilateral facial palsies, hearing loss, bilateral trigeminal nerve dysfunction, oculomotor apraxia, feeding difficulties, seizures, hypotonia, and undeveloped speech. We document a case in which a patient with PTCD presents with a challenging lip deformity and requires multidisciplinary treatment to improve reconstructive surgical success and treatment outcomes. An extensive literature review was conducted. This report serves to increase awareness of PTCD and the need for multidisciplinary teams to participate in reconstruction of facial defects in a complex medical setting.

ACO2 encodes aconitase 2, catalyzing the second step of the tricarboxylic acid. To date, there are only 6 reported families with 5 unique ACO2 mutations. Affected individuals can develop intellectual disability, epilepsy, brain atrophy, hypotonia, ataxia, optic atrophy, and retinal degeneration. Here, we report an 18-year-old boy with a novel ACO2 variant discovered on whole-exome sequencing. He presented with childhood-onset ataxia, impaired self-help skills comparable to severe-profound intellectual disability, intractable epilepsy, cerebellar atrophy, peripheral neuropathy, optic atrophy, and pigmentary retinopathy. His variant is the sixth unique ACO2 mutation. In addition, compared to mild cases (isolated optic atrophy) and severe cases (infantile death), our patient may be moderately affected, evident by increased survival and some preserved cognition (ability to speak full sentences and follow commands), which is a novel presentation. This case expands the disease spectrum to include increased survival with partly spared cognition.

Vitamin D intoxication is uncommon in children and is more commonly suspected in the setting of ingestion of high doses of vitamin D. Its manifestations can be non specific and varied ranging from mild like constipation and vomiting to life threatening like arrhythmias and encephalopathy. Here we present a 14 month female who presented with loss of milestones, floppiness, and poor interaction with mother. She was detected to have hypercalcemia and was subsequently diagnosed with vitamin D intoxication. She was successfully treated with hydration, furosemide, prednisolone and frequent monitoring of electrolytes, electrocardiography and volume status. Subsequently as her serum calcium levels normalized with therapy, she became alert, conscious and started achieving developmental milestones.

Introduction Children with Down syndrome present with joint laxity, hypotonia and shortened hands resulting in reduced grip and pinch strength. Limited information on grip and pinch strength in children with Down syndrome motivated this study. Methods A convenience sample of 30 children with Down syndrome (9–16 years) from special schools and 30 age- and gender-matched healthy school children was studied. Grip and pinch strength were measured according to ASHT standard procedure using JAMAR® dynamometer and B&L pinch gauge. Anthropometric data of upper limb and subject characteristics were recorded. Results Children with Down syndrome had significantly lower values for grip, palmar and key pinch strength (p Conclusions Children with Down syndrome presented with 60% less grip strength, 33% less palmar pinch strength and 22% less key pinch strength when compared to children without Down syndrome. Positive moderate correlation was observed between grip strength, body height, body weight and upper limb anthropometric variables in children with Down syndrome.

ADCY5 mutations have been reported as a cause of early onset hyperkinetic movements associated with delayed motor milestones, hypotonia, and exacerbation during sleep. The movement disorder may be continuous or episodic, and can vary considerably in severity within families and in individuals. The authors report a case series of 3 patients with ADCY5 mutations treated with deep brain stimulation after unsuccessful medication trials. All had extensive imaging, metabolic, and genetic testing prior to confirmation of their ADCY5 mutation. Two of the patients had the c.1252C>T; p.R418W mutation, while the youngest and most severely affected had a de novo c.2080_2088del; p.K694_M696 mutation. All had variable and incomplete, but positive responses to deep brain stimulation. The authors conclude that deep brain stimulation may provide benefit in ADCY5-related movement disorders. Long-term efficacy remains to be confirmed by longitudinal observation. ADCY5 should be considered in the differential diagnosis of early onset hyperkinetic movement disorders, and may respond to deep brain stimulation.

Brain atrophy, white matter abnormalities, and ventricular enlargement have been described in different neuromuscular diseases (NMDs). We aimed to provide a comprehensive overview of the substantial advancement of brain imaging in neuromuscular diseases by consulting the main libraries ( Pubmed, Scopus and Google Scholar) including the more common forms of muscular dystrophies such as dystrophinopathies, dystroglycanopathies, myotonic dystrophies, facioscapulohumeral dystrophy, limb-girdle muscular dystrophy, congenital myotonia, and congenital myopathies. A consistent, widespread cortical and subcortical involvement of grey and white matter was found. Abnormalities in the functional connectivity in brain networks and metabolic alterations were observed with positron emission tomography (PET) and single photon emission computed tomography (SPECT). Pathological brain changes with cognitive dysfunction seemed to be frequently associated in NMDs. In particular, in congenital muscular dystrophies (CMDs), skeletal muscular weakness, severe hypotonia, WM abnormalities, ventricular dilatation and abnormalities in cerebral gyration were observed. In dystroglycanopathy 2I subtype (LGMD2I), adult patients showed subcortical atrophy and a WM periventricular involvement, moderate ventriculomegaly, and enlargement of subarachnoid spaces. Correlations with clinical features have been observed with brain imaging characteristics and alterations were prominent in congenital or childhood onset cases. In myotonic dystrophy type 2 (DM2) symptoms seem to be less severe than in type 1 (DM1). In Duchenne and Becker muscular dystrophies (DMD, BMD) cortical atrophy is associated with minimal ventricular dilatation and WM abnormalities. Late-onset glycogenosis type II (GSD II) or Pompe infantile forms are characterized by delayed myelination. Only in a few cases of oculopharyngeal muscular dystrophy (OPMD) central nervous system involvement has been described and associated with executive functions impairment.

Fazio-Londe syndrome is a rare neurodegenerative disorder caused by riboflavin transporter deficiency. Clinical presentation includes variable hypotonia or muscle weakness, sensory gait ataxia, optic atrophy, sensorineural hearing loss, and bulbar palsies. We described the case of a 37-year-old patient with a suspected Fazio-Londe syndrome who was referred to us for oral incompetence with dysarthria and drooling and impaired facial expression. First, we provided static sling suspension of the lower lip with Silhouette sutures (Silhouette Lift). Due to recurrent sutures exposure, we had to remove the sutures and insert a bilateral fascia lata graft to resuspend the lower lip. Two months postoperatively, the patient had good oral competence and there were no complications. In our opinion, this is a simple and minimally invasive procedure that can restore the right lower lip position in challenging patients.

Mitochondrial DNA (mtDNA) depletion syndrome is a relatively novel cause of hepatic dysfunction in the pediatric population. It is caused by mutations in either mtDNA or nuclear DNA (nDNA) that result in a quantitative reduction in mtDNA and, in turn, dysfunctional oxidative phosphorylation. In infants, it results in the hepatocerebral phenotype, characterized by hyperbilirubinemia, coagulopathy, lactic acidosis, hypoglycemia, lethargy, encephalopathy, developmental delay, and hypotonia. Three infants diagnosed with mtDNA depletion syndrome at The Children's Hospital of Philadelphia were identified, and their clinical presentation, disease course, and histologic and ultrastructural features of liver samples (pre- and postmortem) were characterized. While a different mutant gene was identified in each child, they all showed clinical evidence of metabolic dysfunction soon after birth and expired by 1 year of age. Steatosis, cholestasis, and cytoplasmic crowding by atypical mitochondria were consistent pathologic liver findings. Other findings included hepatocyte hypereosinophilia, fibrosis, and hemosiderosis. This analysis provides insight into the important clinical signs/symptoms and histopathologic and ultrastructural features of mtDNA depletion syndrome in infants and young children. Knowledge of these characteristics will facilitate early recognition and appropriate treatment of this rare disorder. Additionally, ultrastructural evaluation of liver samples by electron microscopy is an important diagnostic component of hepatic dysfunction caused by metabolic abnormalities. This type of analysis should be routinely employed in the setting of unexplained cholestasis, especially when accompanied by steatosis and hepatocyte hypereosinophilia.

Nemaline myopathy is a type of the heterogeneous group of congenital myopathies. Generalized hypotonia, weakness, and delayed motor development are the main clinical features of the typical congenital form. Histopathology shows characteristic nemaline rods in the muscle biopsy. Mutations in at least 7 genes, including nebulin gene ( NEB), proved to be responsible for this muscle disease. We present a boy with nemaline myopathy type 2 (NEM2) caused by compound heterozygosity for 2 novel mutations, a deletion and a duplication in the NEB gene. The deletion was inherited from the father and the duplication from the mother. Testing all family members supports genetic counseling.

Classical lissencephaly may be associated with cerebellar hypoplasia and when significant cerebellar abnormalities occur, defects in proteins encoded by TUBA1A, RELN, and very-low-density lipoprotein receptor ( VLDLR) genes have been reported. We present a neonate with a severe neurologic phenotype associated with hypotonia, oropharyngeal incoordination that required a gastric tube for feeding, intractable epilepsy, and congenital cataracts. Her brain magnetic resonance imaging (MRI) showed classical lissencephaly, ventriculomegaly, absent corpus callosum, globular and vertical hippocampi, and severe cerebellar and brainstem hypoplasia. She died at 6 weeks of age. No specific molecular diagnosis was made. This likely represents a previously undescribed genetic lissencephaly syndrome.

The purpose of this feature is to heighten awareness of specific adverse drug reactions (ADRs), discuss methods of prevention, and promote reporting of ADRs to the US Food and Drug Administration's (FDA's) MEDWATCH program (800-FDA-1088).

This report describes a case of megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome in a 1-year-old boy, born to healthy nonconsanguineous parents. Megalencephaly and bilateral postaxial polydactyly of upper and lower limbs were noted at birth. He had profound developmental delay and moderate hypotonia. Magnetic resonance imaging (MRI) of the brain revealed hydrocephalus, polymicrogyria in both frontal lobes and perisylvian regions, and thin corpus callosum. Array-comparative genomic hybridization was normal. The patient’s clinical and radiologic findings fit the classic description of megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome. The possible overlap between megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome and other similar conditions is discussed.

Purpose Neonatal nonketotic hyperglycinemia is an autosomal recessive inborn disorder of glycine metabolism in which large quantities of glycine accumulate in all body tissues. It is characterized by a progressive lethargy, hypotonia, myoclonic jerks, and early death secondary to respiratory problems. As a result of early diagnosis and treatment protocols, more patients survive the critical neonatal period with profound mental retardation, delayed developmental milestones, seizures, and spasticity. There are no reports about the orthopaedic manifestations of neonatal nonketotic hyperglycinemia. The purpose of this study is to evaluate the musculoskeletal findings of neonatal nonketotic hyperglycinemia. Methods This is a retrospective IRB-approved study of all patients in our Orthopaedic and Genetics Clinics with the diagnosis of neonatal nonketotic hyperglycinemia during a 10-year period. Demographic, clinical, and imaging data were analyzed. Results Twelve patients with neonatal nonketotic hyperglycinemia were evaluated, with a mean age of 7 years and 2 months (range: 5 months to 21 years). Seven were male and five were female. Eleven patients (92 %) have evidence of progressive early-onset neuromuscular scoliosis with a mean Cobb angle of 55° (range: 30–95°). Five children (42 %) presented evidence of progressive hip dislocation secondary to spasticity. All the patients have severe multiple joint contractures. Conclusion Neonatal nonketotic hyperglycinemia is a rare metabolic disorder presented in the past as a lethal condition. Recent advances in early diagnosis and neonatal care improve overall outcome. As pediatric orthopaedic surgeons, we need to establish treatment based on update information of the disease and probability to improve quality of life.

Pitt-Hopkins syndrome is characterized by marked intellectual impairment, hyperventilation episodes, and dysmorphic facial features. This article reports a boy who presented with developmental delay, facial dysmorphism, microcephaly, hypotonia, and areflexia. He was initially diagnosed with Charcot Marie Tooth disease type 1A based on family history and genetic testing. However, severe mental impairment was atypical of Charcot Marie Tooth disease type 1A. Over the next few years he developed characteristic breathing abnormality, hand stereotypies, seizures, and marked constipation. The evolution of these manifestations coupled with the characteristic facial appearance suggested the additional diagnosis of Pitt-Hopkins syndrome, which was confirmed by the genetic defect of the transcription factor 4 on chromosome 18. This case demonstrates the rare co-occurrence of 2 genetic disorders in the same individual.

Cerebellar hypoplasia is the hallmark of a heterogeneous group of disorders that are caused by genetic and metabolic disorders. Prenatal identification of cerebellar hypoplasia and accurate prediction of outcome are challenging. Autosomal dominant nonprogressive cerebellar ataxia is a rare disorder that typically presents with early hypotonia and delayed motor milestones followed by the onset of mild ataxia and occasionally cognitive impairment. We present a case of a mother and her female fetus. Fetal sonography and magnetic resonance imaging (MRI) showed generalized cerebellar hypoplasia. The mother had mild learning difficulties and clinically showed minor features of cerebellar ataxia. Her MRI also demonstrated extreme cerebellar hypoplasia. The diagnosis of autosomal dominant nonprogressive cerebellar ataxia was suggested. This is the first report of prenatal diagnosis of autosomal dominant nonprogressive cerebellar ataxia. We recommend obtaining a family history, examining the parents, and when appropriate obtaining an MRI before counseling parents of a fetus with a brain malformation.

Vitamin D-dependent rickets type 1 is an autosomal recessive disorder caused by an inactivating mutation of the 25-hydroxyvitamin-D-1α-hydroxylase (CYP27B1) gene. Clinical presentation is characterized by early onset of severe rickets and can include severe hypotonia. Here, we report a 16-month-old white male who presented with severe muscle weakness, failure to thrive, renal tubular dysfunction, and skeletal deformities, including osteopenia and multiple fractures. At presentation, he had severe hypocalcemia, hypophosphatemia, hypomagnesemia, and elevated alkaline phosphatase and parathyroid hormone levels, although normal 25-hydroxyvitamin D levels. DNA sequencing of the CYP27B1 gene revealed a novel mutation in exon 2 (c286_300de115) and a previously reported mutation in exon 7 (c.1166G>A). Once calcitriol therapy was initiated, the patient showed significant improvement in muscle strength and linear growth. Serum calcium, phosphorous, and alkaline phosphatase returned to normal range. Organic aciduria resolved and aminoaciduria significantly improved 2 months after parathyroid hormone levels normalized.

Acute disseminated encephalomyelitis is an extremely rare occurrence in human immunodeficiency virus (HIV) infection. We describe an 8-year-old male child who presented with weakness of both lower limbs for 10 days and focal convulsions for 2 days. The child had left, upper motor neuron facial palsy, lower limb hypotonia, and exaggerated deep tendon reflexes. Enzyme-linked immunosorbent assay antibodies for HIV tested positive and the CD4 count was 109 cells/µL. The magnetic resonance imaging (MRI, brain) revealed extensive confluent hyperintensities (on T2-weighted images) in left parietal, right temporal, and right occipital regions of the white matter, and similar signals were seen in right lentiform nucleus and right posterior thalami, suggesting acute disseminated encephalomyelitis. There was transient improvement with intravenous methyl prednisolone. The patient succumbed to the illness. Perinatally transmitted pediatric HIV infection presenting with acute disseminated encephalomyelitis has not yet been reported in the medical literature.

The combination of pontocerebellar hypoplasia and anterior horn cell degeneration is classified as pontocerebellar hypoplasia type 1. Although most cases exhibit severe muscle weakness and hypotonia neonatally with short life spans, some cases exhibit a later onset with a longer life span and show cerebellar atrophy without pontine involvement. We present a child who exhibited neurological deterioration and progressive atrophy of the cerebellum and pons, with onset of symptoms at 20 months and death at 15 years of age. The pathological findings disclosed anterior horn cell degeneration and pyramidal tract involvement in addition to pontocerebellar atrophy, leading to the diagnosis of pontocerebellar hypoplasia type 1. The present case suggests that the degenerative pattern of later-onset pontocerebellar hypoplasia type 1 is similar to that of prenatal-onset cases. Further reports of later-onset cases with histopathological examination are required to elucidate the nosology and etiology of the disorder.

The authors report a child with spinal muscular atrophy with respiratory distress type 1 (SMARD1). She presented atypically with hypothyroidism and heart failure due to septal defects that required early heart surgery and microcephaly in association with cerebral atrophy and thin corpus collosum. The subsequent asymmetrical onset of diaphragmatic paralysis, persistent hypotonia, and generalized muscle weakness led to the suspicion of spinal muscular atrophy with respiratory distress type 1. Sanger sequencing confirmed a compound heterozygous mutation in the Immunoglobulin Mu Binding Protein 2 (IGHMBP2) gene, with a known mutation c.2362C > T (p.Arg788*) and a novel frameshift mutation c.2048delG (p.Gly683A1afs*50). Serial nerve conduction study and electromyography confirmed progressive sensorimotor polyneuropathy and neuronopathy. In summary, this case report describes a child with spinal muscular atrophy with respiratory distress type 1 also with congenital cardiac disease and endocrine dysfunction, expanding the phenotypic spectrum of this condition. A high index of suspicion is needed in diagnosing this rare condition to guide the management and genetic counseling.

Dysequilibrium syndrome is a genetically heterogeneous condition that combines autosomal recessive, nonprogressive cerebellar ataxia with mental retardation. Here, we report the first patient heterozygous for 2 novel mutations in VLDLR. An 18-month-old girl presented with significant hypotonia, global developmental delay, and truncal and peripheral ataxia. Magnetic resonance imaging of the brain demonstrated hypoplasia of the inferior cerebellar vermis and hemispheres, small pons, and a simplified cortical sulcation pattern. Sequence analysis of the VLDLR gene identified a nonsense and missense mutation. Six mutations in VLDLR have now been identified in 5 families with a phenotype characterized by moderate-to-profound mental retardation, delayed ambulation, truncal and peripheral ataxia, and occasional seizures. Neuroanatomically, the loss-of-function effect of the different mutations is indistinguishable. VLDLR-associated cerebellar hypoplasia is emerging as a panethnic, clinically, and molecularly well-defined genetic syndrome.

Ethylmalonic encephalopathy is a recently described inborn error of metabolism characterized clinically by developmental delay and regression, recurrent petechiae, orthostatic acrocyanosis, and chronic diarrhea. We describe monochorionic twins presenting with hypotonia in infancy and diagnosed with ethylmalonic encephalopathy on the basis of biochemical findings. They are compound heterozygote for missense mutations in ETHE1. Magnetic resonance imaging changes affecting the white matter, corpus callosum, and basal ganglia were seen in both patients. At 10 years of age, they have severe axial hypotonia but never displayed petechiae, orthostatic acrocyanosis, or chronic diarrhea. Their clinical courses differ markedly; one had an episode of coma when she was 3 years old and now has spastic quadraparesis and cannot speak. The other can freely use her upper extremities, her pyramidal syndrome being mostly limited to the lower extremities, and can speak 2 languages. These patients illustrate the clinical heterogeneity of ethylmalonic encephalopathy, even in monochorionic twins.

Myotonic dystrophy is considered a true dominant condition with no difference in the phenotype between heterozygous and homozygous cases. The homozygous state is very rare and only a few patients have been reported in the literature. We report a 2.5-year-old boy from a nonconsanguineous marriage, with a unique combination of clinical and radiological findings: hypotonia, motor and language developmental delay, ventriculomegaly, subcortical white matter lesions, and craniosynostosis. Mutation analysis revealed 2 copies of expansion mutation of 1260 and 60 cytosine-thymine-guanine repeats in the myotonic dystrophy protein kinase gene. Both the mildly symptomatic (434 repeats) mother and the asymptomatic (37 repeats) father are heterozygous. Craniosynostosis has not been reported previously in myotonic dystrophy. This homozygous case expands the clinical spectrum of myotonic dystrophy type 1 and provides support to the hypothesis that myotonic dystrophy type 1 pathophysiology could be, in part, due to the loss of normal function of the wild-type protein.

Macrophagic myofasciitis is a novel, “inflammatory myopathy” described after a variety of vaccinations, almost exclusively in adults. We examined the relevance of histological findings of this myopathy to the clinical presentation in pediatric patients. Muscle biopsies from 8 children (7 months to 6 years old) with histological features of macrophagic myofasciitis were reviewed and correlated with the clinical manifestations. Patients underwent quadriceps muscle biopsy for suspected mitochondrial disease (4 patients), spinal muscular atrophy (2 patients), myoglobinuria (1 patient), and hypotonia with motor delay (1 patient). All biopsies showed identical granulomas composed of periodic acid-Schiff—positive and CD68-positive macrophages. Characteristic aluminum hydroxide crystals were identified by electron microscopy in 2 cases. The biopsy established diagnoses other than macrophagic myofasciitis in 5 patients: spinal muscular atrophy (2), Duchenne muscular dystrophy (1), phospho-glycerate kinase deficiency (1), and cytochrome c oxidase deficiency (1). Three children with manifestations and/or a family history of mitochondrial disease had otherwise morphologically normal muscle. All children had routine vaccinations between 2 months and 1 year before the biopsy, with up to 11 intramuscular injections, including the biopsy sites. There was no correlation between histological findings of macrophagic myofasciitis in biopsies and the clinical symptoms. We believe that macrophagic myofasciitis represents a localized histological hallmark of previous immunization with the aluminum hydroxide adjuvants contained in vaccines, rather than a primary or distinct inflammatory muscle disease.

Prader-Willi syndrome, the first known human genomic imprinting disorder, is one of the most common micro-deletion syndromes. Prader-Willi syndrome is caused by the absence of certain paternally inherited genes on the long arm of chromosome 15, resulting in a complete absence of the active copy of the genetic information in this region. It is most commonly known for its food-related characteristics of hyperphagia, food-seeking behavior, and consequent obesity. Primary care physicians play an important role in the care of children with Prader-Willi syndrome, from recognizing the presenting signs and symptoms at its various stages to understanding their unique medical, developmental, behavioral, and dietary issues. They can also serve as a valuable source of support and advocacy for the family. This article reviews the current state of knowledge about Prader-Willi syndrome and discusses up-to-date understanding of the management of this condition.

The neurologic manifestations of patients with phenylketonuria treated at different ages are illustrated in this series of 146 cases, including 9 sib pairs. In addition to well-known findings such as mental retardation, autistic features, microcephaly, and tremor, motor retardation was common and responded promptly to dietary treatment. Hypotonia and diminished reflexes were more frequent findings than hypertonia. Four sib pairs showed divergent features, such as the later-treated sibling having higher function than the early-treated one. Because siblings have a similar genotype and similar environmental and dietary conditions, this observation can be explained by differences in phenylalanine transport to the brain or additional metabolic or perinatal factors influencing the neurologic outcome. (J Child Neurol 2006;21:987—990; DOI 10.2310/7010.2006.00228).

We report a case of partial biotinidase deficiency (plasma biotinidase levels: 1.30 nm/minute/mL) in a 7-month-old boy who presented with evidence of perinatal distress followed by developmental delay, hypotonia, seizures, and infantile spasms without alopecia or dermatitis. His neurologic symptoms improved markedly on biotin supplementation and antiepileptic drug therapy. DNA mutational analysis revealed that the patient was homozygous for a novel E64K mutation and his parents were heterozygous for the same mutation. Whereas preexisting perinatal distress probably contributed to the severity of the patient's symptoms, the described mutation is novel and is possibly responsible for at least some of his clinical manifestations. (J Child Neurol 2006;21:978-981; DOI 10.2310/ 7010.2006.00200).

In 1911, Oppenheim coined the term ‘dystonia’ to describe disordered motor control, characterised by an association of hypotonia and tonic muscle spasm. Focal hand dystonia is one form of this disorder, in which symptoms are often task-specific and occur during skilled movements such as writing (writer's cramp) or playing a musical instrument (musician's cramp). Much research has been conducted on the pathophysiology of dystonia, but the underlying mechanisms still remain unclear. Hypotheseses about functional central nervous system alterations continue to gain more support. Scientific treatment-based publications on focal dystonia are sparse, and progress in evidence-based treatment options are necessary in order to assist this patient group. This paper will review the literature, documenting dystonia classification criteria, manifestations, pathophysiology and medical treatment techniques for musicians affected by focal hand dystonia.

Central core disease is a nonprogressive or slowly progressive congenital myopathy with a variable degree of hypotonia and axial and proximal muscle weakness that is histologically characterized by areas devoid of oxidative enzyme activity, resulting from an absence or low numbers of mitochondria in these regions (central core). A 10-month-old, male, pony foal was examined because of stiff gait, marked contractures of the distal portion of the limbs, flexion deformities of the hooves, and moderate hypotonia that had been present from birth. The foal had increased creatine kinase (282 U/ liter; reference interval 10-135 U/liter), lactate dehydrogenase (1,188 U/liter; reference interval 150–450 U/liter), and aspartate transaminase (377 U/liter; reference interval

We studied the effects of hyperbilirubinemia on brainstem auditory pathways and neurodevelopmental status in 99 fullterm neonates with severe nonhemolytic hyperbilirubinemia (total serum bilirubin level = 301 to 500 µmol/L) born between 1995 and 2000. These were divided into three groups: group 1, moderate hyperbilirubinemia ( n = 30; mean maximum total serum bilirubin = 320.7 µmol/L or 18.9 mg%); group 2, severe hyperbilirubinemia ( n= 63; mean maximum total serum bilirubin = 369.0 µmol/L or 21.7 mg%); and group 3, super hyperbilirubinemia ( n = 6; mean maximum total serum bilirubin = 457.2 µmol/L or 26.9 mg%). All received phototherapy, and three neonates also had exchange transfusion. Initial brainstem auditory evoked potentials were recorded in all at the mean age of 3.1 months (range 1—9 months). At initial assessment, only nine neonates (9.1%) had abnormal brainstem auditory evoked potentials. All except two returned to normal at 2 years. These two children had a hearing threshold at 50 nHL. We then compared serial brainstem auditory evoked potentials until 2 years for these nine cases with initial abnormal brainstem auditory evoked potentials, and nine cases with initial normal brainstem auditory evoked potentials were recruited for comparison. All 99 children had regular physical, neurologic, visual, and auditory assessments every 3 to 6 months until the age of 3 years. There was no significant correlation between demographic factors (gender, gestational age, or birthweight), maximum total serum bilirubin, and total serum bilirubin at discharge with an abnormal brainstem auditory evoked potential. There was no significant difference in the rate of brainstem auditory evoked potential abnormalities between the three groups: moderate (10%), severe (7.9%), and super (16.7%). All had normal neurodevelopmental status at 3 years. Only two children had transient mild motor delay and hypotonia, and both had normal brainstem auditory evoked potentials. There was no relationship between the abnormalities of the brainstem auditory evoked potentials and neurodevelopmental status. None of the three children receiving exchange transfusion had abnormal brainstem auditory evoked potentials or neurodevelopmental outcome. With the neurophysiologic and clinical outcomes in our cohort with severe nonhemolytic hyperbilirubinemia, we propose that the toxic effect of hyperbilirubinemia on auditory brainstem pathways might be transient provided that prompt treatment is initiated. ( J Child Neurol 2006;21:309—315; DOI 10.2310/7010.2006.00058).

Joubert syndrome was first described in 1969. It is a rare inherited disorder demonstrating one of the developmental defects of the cerebellar vermis. The main clinical signs of the syndome include developmental delay, hypotonia, ataxia, abnormal ocular movements and abnormal respiratory pattern of alternating episodic tachypnea-hyperpnea and apnea. Radiological findings comprise a midline cerebellar cleft in place of the vermis and a characteristic shape of the fourth ventricule. Associated supratentorial abnormalities such as callosal dysgenesis have been infrequently reported in patients with Joubert syndrome This report describes the clinical and neuroradiological findings of a rare patient presenting Joubert syndrome associated with total corpus callosum agenesis.

Rett syndrome is a unique neurodevelopmental disorder, with onset of hypotonia, autistic tendency, and abnormalities of fine finger movements and gross movements of the arms in early infancy. Clinical features include specific age-dependent symptoms. Studies of early and late signs correlated locomotive dysfunction to language disability and stereotypy to regression of higher cortical functions. Studies of sleep parameters revealed early hypofunction of brainstem aminergic neurons and late occurrence of hypofunction of dopaminergic neurons, followed by receptor supersensitivity. The syndrome's pathophysiology suggests that early hypofunction of aminergic neurons interferes with the development of higher neuronal systems. Particular symptoms surface at different ages throughout the natural course of Rett syndrome, with regressional and static periods. ( J Child Neurol 2005;20:764—768).

Breastfeeding is the gold standard when it comes to infant feeding due to the significant health benefits it offers infants. The advantages of breast milk are even greater for infants with Down syndrome because of their increased risk for infections and gastrointestinal issues. However, because babies with Down syndrome often experience unique challenges that can compromise successful breastfeeding, the hospital uses special techniques in the nursery to ensure the mothers have the necessary education to initiate breastfeeding and to troubleshoot should problems arise. The techniques outlined are designed to address issues of hypotonia, sleepiness, and tongue thrusting, which are common in babies with Down syndrome.

This study was performed with the aim of determining the diagnostic profile of newborns with hypotonia and of analyzing the usefulness of different procedures in the diagnostic process. One hundred thirty-eight hypotonic newborns were identified through the search of hospital records in a 10-year period: 121 (88%) had central hypotonia and 13 (9%) had peripheral hypotonia, whereas 4 (3%) remained unclassified. Analysis of the contribution of clinical data and results of investigations led to the construction of an algorithm, by which all cases in the group were diagnosed. Step 1, which included clinical data and results of examinations, solved 50% of all diagnosed cases. Neuroimaging techniques made up step 2 and contributed to the diagnosis in 13%. Step 3 was accomplished by a search through Oxford Medical Databases, which yielded the final diagnosis in 9%, whereas karyotyping and fluorescent in situ hybridization for Prader-Willi syndrome comprised step 4 and contributed to the diagnosis in 6.5%. Biochemical tests formed step 5 and contributed to the diagnosis in 6%. Step 6, which included specific investigations of muscle and nerve, was diagnostic in 6%. The remaining cases (6.5%) were diagnosed only after several follow-up examinations. These results could assist the neonatologist when deciding the diagnostic approach to floppy newborns. ( J Child Neurol 2004;19:439-442).

Pelizaeus-Merzbacher disease is a rare X-linked disease characterized by defective central nervous system myelination owing to a mutation in the proteolipid protein 1 gene. Few studies report detailed clinical findings in children with genetic confirmation of mutations in the proteolipid protein 1 gene. We reviewed the records of 10 boys with Pelizaeus-Merzbacher disease and one symptomatic carrier girl. Their median age was 2½ years (range 10 months to 20 years). Nine had proteolipid protein 1 gene duplications, one had a point mutation, and one had a single codon deletion. The families of eight patients reported perinatal complications, including maternal hypertension (three patients) and meconium aspiration (three patients). All of the patients were social and interactive, but all had difficulty with expressive speech. All patients presented with nystagmus and had hypotonia that progressed to spasticity, affecting the legs more than the arms; ataxia also contributed to motor impairment. Additional problems reported regarded feeding (eight patients) and sleep (three patients). Further work is needed to clarify the variations in disease course and the relationship of genotype to phenotype. (J Child Neurol 2004;19:328-331).

Pontocerebellar hypoplasia type 1 is a rare disease characterized by pontocerebellar hypoplasia and anterior horn cell degeneration. The oldest reported child died at the age of 26 months. Two siblings were diagnosed with pontocerebellar hypoplasia type 1 after the death of the second sibling at 40 months of age from respiratory failure and the unexpected finding of anterior horn cell degeneration on her autopsy. The older sibling was a boy who was labeled as having cerebral palsy. He died at 14 months of age from pneumonia following a clinical course similar to his sister's, who was born 5 years after his death. Both siblings had significant global developmental delay with axial and peripheral hypotonia initially. Peripheral hypertonia with brisk reflexes developed later but were absent prior to death. Extensive investigations in the second sibling ruled out known metabolic (including congenital disorders of glycosylation) and mitochondrial diseases using skin fibroblast cultures and enzyme analysis. Genetic testing for Friedreich's ataxia; neuropathy, ataxia, and retinitis pigmentosa (NARP); spinal muscular atrophy; and spinocerebellar ataxia type 1, 2, 3, 6, 7, and 8 gene abnormalities was negative. The electroretinogram showed a previously unreported finding of abnormal and progressive rod/cone response. Our cases provide clinical and previously unreported electroretinographic evidence for neuro-degeneration in pontocerebellar hypoplasia type 1 and call for the expansion of the disease phenotype. ( J Child Neurol 2003; 18:220—225).

Movement disorders, a common problem in children with neurologic impairment, are receiving increasing clinical attention. The differences in movement disorders between adults and children are striking; presentation is frequently insidious and may be characterized by mild hypotonia. The clinical manifestations of extrapyramidal disorders are profoundly influenced by the age of onset. The conditions reviewed in this article are expressed clinically by the occurrence of abnormalities of movement and posture, often in association with disturbances of muscle tone. This article reviews empiric drug use and recommendations for childhood movement disorders. (J Child Neurol 2003;18:S40—S49).

Fumarase deficiency is a very rare inborn error of metabolism caused by decreased activity of fumarate hydratase enzyme. We describe a fumarase-deficient infant who presented with encephalopathy, metabolic crisis, psychomotor retardation, hypotonia, seizures, and facial dysmorphism. To our knowledge, this is the first Indian child to be described with fumarase deficiency.

A group of 12 children clinically presenting with hypotonia, intractable epilepsy, autism, and developmental delay, who did not fall into previously described categories of mitochondrial encephalomyopathy, were evaluated for mitochondrial respiratory enzyme activity levels, mitochondrial DNA, and mitochondrial structural abnormalities. Reduced levels in specific respiratory activities were found solely in enzymes with subunits encoded by mitochondrial DNA in seven of eight biopsied skeletal muscle specimens evaluated. Five cases exhibited increased levels of large-scale mitochondrial DNA deletions, whereas pathogenic point mutations previously described in association with mitochondrial encephalomyopathies were not found. Mitochondrial structural abnormalities were present in three of four patients examined. Our findings suggest that mitochondrial dysfunction, including extensive abnormalities in specific enzyme activities, mitochondrial structure, and mitochondrial DNA integrity, may be present in children with a clinical constellation including hypotonia, epileptic seizures, autism, and developmental delay. The acronym HEADD is presented here to facilitate pursuit of mitochondrial defects in patients with this clinical constellation after other causes have been excluded. (J Child Neurol 2002;17:435-439).

The Glutamate receptor, ionotropic, delta 2 gene codes for an ionotropic glutamate delta-2 receptor, which is selectively expressed in cerebellar Purkinje cells, and facilitates cerebellar synapse organization and transmission. The phenotype associated with the deletion of Glutamate receptor, ionotropic, delta 2 gene in humans was initially defined in 2013. In this case report, the authors describe 2 brothers who presented with developmental delay, tonic upward gaze, nystagmus, oculomotor apraxia, hypotonia, hyperreflexia, and ataxia. They were found to have a homozygous intragenic deletion within the Glutamate receptor, ionotropic, delta 2 gene at exon 2. Our patients serve as an addition to the literature of previously reported children with this rare clinical syndrome associated with Glutamate receptor, ionotropic, delta 2 deletion.