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The study aimed at widening the clinical and genetic spectrum of ASXL3-related syndrome, a neurodevelopmental disorder, caused by truncating variants in the ASXL3 gene. In this international collaborative study, we have undertaken a detailed clinical and molecular analysis of 45 previously unpublished individuals with ASXL3-related syndrome, as well as a review of all previously published individuals. We have reviewed the rather limited functional characterization of pathogenic variants in ASXL3 and discuss current understanding of the consequences of the different ASXL3 variants. In this comprehensive analysis of ASXL3-related syndrome, we define its natural history and clinical evolution occurring with age. We report familial ASXL3 pathogenic variants, characterize the phenotype in mildly affected individuals and discuss nonpenetrance. We also discuss the role of missense variants in ASXL3. We delineate a variable but consistent phenotype. The most characteristic features are neurodevelopmental delay with consistently limited speech, significant neuro-behavioral issues, hypotonia, and feeding difficulties. Distinctive features include downslanting palpebral fissures, hypertelorism, tubular nose with a prominent nasal bridge, and low-hanging columella. The presented data will inform clinical management of individuals with ASXL3-related syndrome and improve interpretation of new ASXL3 sequence variants.

There has been one previous report of a cohort of patients with variants in Chromodomain Helicase DNA-binding 3 (CHD3), now recognized as Snijders Blok-Campeau syndrome. However, with only three previously-reported patients with variants outside the ATPase/helicase domain, it was unclear if variants outside of this domain caused a clinically similar phenotype. We have analyzed 24 new patients with CHD3 variants, including nine outside the ATPase/helicase domain. All patients were detected with unbiased molecular genetic methods. There is not a significant difference in the clinical or facial features of patients with variants in or outside this domain. These additional patients further expand the clinical and molecular data associated with CHD3 variants. Importantly we conclude that there is not a significant difference in the phenotypic features of patients with various molecular disruptions, including whole gene deletions and duplications, and missense variants outside the ATPase/helicase domain. This data will aid both clinical geneticists and molecular geneticists in the diagnosis of this emerging syndrome.

Inborn errors of metabolism affect approximately 1 in 1,000 to 1 in 3,000 live births. Most of these inherited conditions are autosomal recessive, although a few are autosomal dominant or X-linked. Mitochondrial DNA disorders may be maternally inherited. The clinical symptoms associated with inborn errors of metabolism reflect the disruption of normal biochemical processes required for synthesis, breakdown, or transport of metabolites. This impairment leads to accumulation of metabolites that cause toxic effects, inadequate levels of metabolites required for normal cellular activity, or secondary disruption of essential metabolic pathways. Small molecule disorders involve the metabolism of amino acids, organic acids, carbohydrates, fatty acids, and other biochemical pathways. These disorders may present with acute exacerbations superimposed on long-term neurologic symptoms.

Leukoencephalopathies are disorders that selectively involve the white matter of the brain. Acquired causes of leukoencephalopathy include inflammatory, infectious, vascular, neoplastic, and toxic disorders. Hereditary leukoencephalopathies encompass conditions characterized by progressive destruction or loss of previously acquired central myelin (leukodystrophies) and conditions associated with impaired formation of myelin (dysmyelination or hypomyelination). The study of clinical features, neuroimaging patterns, and biochemical and neuropathologic features of leukoencephalopathies has led to the discovery of the genetic defects responsible for many of these conditions. Variations in phenotype-genotype correlation can make prediction of the underlying condition challenging. Despite recent advances in molecular studies, approximately 50% of patients with hereditary leukoencephalopathies remain without a diagnosis. A systematic approach to guide investigations is important for a diagnosis.

Key Clinical Message We report a patient with developmental delay, autism, epilepsy, macrocephaly, facial dysmorphism, gastrointestinal, and behavioral issues due to EXT2 compound heterozygous likely pathogenic variants. This case report expands the EXT2 gene mutation database and the clinical spectrum of patients with deficiencies in the heparan sulfate pathway.

Pathogenic variants in Lysyl-tRNA synthetase 1 (KARS1) have increasingly been recognized as a cause of early-onset complex neurological phenotypes. To advance the timely diagnosis of KARS1-related disorders, we sought to delineate its phenotype and generate a disease model to understand its function in vivo. Through international collaboration, we identified 22 affected individuals from 16 unrelated families harboring biallelic likely pathogenic or pathogenic in KARS1 variants. Sequencing approaches ranged from disease-specific panels to genome sequencing. We generated loss-of-function alleles in zebrafish. We identify ten new and four known biallelic missense variants in KARS1 presenting with a moderate-to-severe developmental delay, progressive neurological and neurosensory abnormalities, and variable white matter involvement. We describe novel KARS1-associated signs such as autism, hyperactive behavior, pontine hypoplasia, and cerebellar atrophy with prevalent vermian involvement. Loss of kars1 leads to upregulation of p53, tissue-specific apoptosis, and downregulation of neurodevelopmental related genes, recapitulating key tissue-specific disease phenotypes of patients. Inhibition of p53 rescued several defects of kars1−/− knockouts. Our work delineates the clinical spectrum associated with KARS1 defects and provides a novel animal model for KARS1-related human diseases revealing p53 signaling components as potential therapeutic targets.

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.

To our knowledge, we detail the first case of a phenotypic expression of Leber hereditary optic neuropathy plus caused by a nuclear gene mutation in a 22-year-old female with painless, bilateral, sequential vision loss and dystonia associated with heterozygous mutations in the NDUFAF5 gene.

Objective We describe the clinical characteristics and genetic etiology of several new cases within the ACO2‐related disease spectrum. Mitochondrial aconitase (ACO2) is a nuclear‐encoded tricarboxylic acid cycle enzyme. Homozygous pathogenic missense variants in the ACO2 gene were initially associated with infantile degeneration of the cerebrum, cerebellum, and retina, resulting in profound intellectual and developmental disability and early death. Subsequent studies have identified a range of homozygous and compound heterozygous pathogenic missense, nonsense, frameshift, and splice‐site ACO2 variants in patients with a spectrum of clinical manifestations and disease severities. Methods We describe a cohort of five novel patients with biallelic pathogenic variants in ACO2. We review the clinical histories of these patients as well as the molecular and functional characterization of the associated ACO2 variants and compare with those described previously in the literature. Results Two siblings with relatively mild symptoms presented with episodic ataxia, mild developmental delays, severe dysarthria, and behavioral abnormalities including hyperactivity and depressive symptoms with generalized anxiety. One patient presented with the classic form with cerebellar hypoplasia, ataxia, seizures, optic atrophy, and retinitis pigmentosa. Another unrelated patient presented with ataxia but developed severe progressive spastic quadriplegia. Another patient demonstrated a spinal muscular atrophy‐like presentation with severe neonatal hypotonia, diminished reflexes, and poor respiratory drive, leading to ventilator dependence until death at the age of 9 months. Interpretation In this study, we highlight the importance of recognizing milder forms of the disorder, which may escape detection due to atypical disease presentation.

Background: The dynamin 1-like gene ( DNM1L) encodes a GTPase that mediates mitochondrial and peroxisomal fission and fusion. We report a new clinical presentation associated with a DNM1L pathogenic variant and review the literature. Results: A 13-year-old boy with mild developmental delays and paroxysmal dystonia presented acutely with multifocal myoclonic super-refractory status epilepticus. Despite sustained and aggressive treatment, seizures persisted and care was ultimately withdrawn in the context of extensive global cortical atrophy. Rapid trio-whole exome sequencing revealed a de novo heterozygous c.1207C>T (p.R403C) pathogenic variant in DNM1L. Immunofluorescence staining of fibroblast mitochondria revealed abnormally elongated and tubular morphology. Conclusions: This case highlights the diagnostic importance of rapid whole exome sequencing within a critical care setting and reveals the expanding phenotypic spectrum associated with DNM1L variants. This now includes progressive paroxysmal dystonia and adolescent-onset super-refractory myoclonic status epilepticus contributing to strikingly rapid and progressive cortical atrophy and death.

Internal carotid artery pseudoaneurysm is an uncommon complication of retropharyngeal and parapharyngeal abscess in children. Treatment of the pseudoaneurysm has evolved in recent years from surgical ligation to endovascular techniques. Neurologic sequelae most commonly consist of Horner’s syndrome with cerebral ischemia being uncommon. The clinical course of a 2-year-old boy with retropharyngeal abscess complicated by internal carotid artery pseudoaneurysm, is described and the literature is reviewed. A conventional angiogram confirmed the presence of a large pseudoaneurysm with no anterograde flow distal to the pseudoaneurysm and substantial collateral flow across the circle of Willis, with filling of the left anterior and middle cerebral arteries via the anterior and posterior communicating arteries. Endovascular occlusion resulted in nonfilling of the left internal carotid artery, pseudoaneurysm, and left internal jugular vein at the base of the skull. Following the procedure, the patient developed transient mild right hemiparesis associated with frontal lobe ischemia.

This article describes the clinical, genetic, and radiographic features of inherited leukoencephalopathies presenting in adulthood.In recent years, the molecular basis for several inherited leukoencephalopathies, presenting exclusively in adults, has been discovered. Inherited leukoencephalopathies, previously described in children, have been found to have milder or later onset forms presenting in adults.Although individually rare, inherited leukoencephalopathies are important to consider in the differential diagnosis of cognitive decline. Patients with inherited leukoencephalopathies frequently present to multiple sclerosis and dementia clinics. Clinical and radiographic features can be used to guide investigations in these patients.

Limited information is known about neuropsychological outcomes in Alexander disease, a rare leukodystrophy. Two pediatric cases are summarized. Case 1 (evaluations at 6, 7, 9, and 12 years of age) represents Type I Alexander disease with associated seizures. Case 2 (evaluations at 12, 13, and 16 years of age) represents Type II Alexander disease without additional complications. Case 1 experienced declines in intellectual functioning, visual motor skills, receptive vocabulary, verbal memory, and academic achievement. Case 2 experienced variable neurocognitive change and academic functioning, with average word reading and spelling. Verbal memory also remained intact. Taken together, individuals with Alexander disease may experience cognitive decline to variable degrees. Type I Alexander disease, associated with earlier onset and additional neurological complications, may presage greater cognitive decline than Type II. Due to variability in functioning over time, it is critical to follow individuals across development to make recommendations for educational and treatment planning.

ObjectiveTo expand the phenotypic spectrum of severity of POLR3-related leukodystrophy and identify genotype-phenotype correlations through study of patients with extremely severe phenotypes.MethodsWe performed an international cross-sectional study on patients with genetically proven POLR3-related leukodystrophy and atypical phenotypes to identify 6 children, 3 males and 3 females, with an extremely severe phenotype compared with that typically reported. Clinical, radiologic, and molecular features were evaluated for all patients, and functional and neuropathologic studies were performed on 1 patient.ResultsEach patient presented between 1 and 3 months of age with failure to thrive, severe dysphagia, and developmental delay. Four of the 6 children died before age 3 years. MRI of all patients revealed a novel pattern with atypical characteristics, including progressive basal ganglia and thalami abnormalities. Neuropathologic studies revealed patchy areas of decreased myelin in the cerebral hemispheres, cerebellum, brainstem, and spinal cord, with astrocytic gliosis in the white matter and microglial activation. Cellular vacuolization was observed in the thalamus and basal ganglia, and neuronal loss was evident in the putamen and caudate. Genotypic similarities were also present between all 6 patients, with one allele containing a POLR3A variant causing a premature stop codon and the other containing a specific intronic splicing variant (c.1771-7C>G), which produces 2 aberrant transcripts along with some wild-type transcript.ConclusionsWe describe genotype-phenotype correlations at the extreme end of severity of the POLR3-related leukodystrophy spectrum and shed light on the complex disease pathophysiology.

X-linked adrenoleukodystrophy is a peroxisomal disorder caused by a mutation in ABCD1 gene. The three main phenotypes of X-linked adrenoleukodystrophy include cerebral adrenoleukodystrophy, adrenomyeloneuropathy, and isolated primary adrenal insufficiency. More than 750 non-recurrent mutations exist throughout the coding region of the ABCD1 gene. We report a 62-year-old man with a 17-year history of progressive gait imbalance and numb feet. He had noted difficulty rising from a chair for 3 years. Examination revealed proximal lower limb weakness and length-dependent sensory loss with preservation of reflexes and unilateral Babinski sign. Electrodiagnostic evaluation confirmed a length-dependent sensorimotor peripheral neuropathy and proximal myopathy. Family history was remarkable for similar symptoms in 6 siblings. A targeted gene approach for 102 known peripheral neuropathy genes led to discovery of ABCD1 mutation confirmed by kindred evaluation and biochemical assay. This case highlights the importance of combining targeted gene approaches with functional assay confirmation especially for atypical clinical presentations.

Hutchinson-Gilford progeria syndrome is an autosomal dominant condition, which presents in early childhood with symptoms of premature aging and early death. The allelic disorder, mandibuloacral dysplasia is a disorder with progeroid facial appearance, mandibular hypoplasia and acro-osteolysis. These two diseases have been considered different clinical entities based on differences in phenotype and inheritance pattern but are both due to mutations in the lamin A/C (LMNA) gene. Differentiating the diseases clinically can be difficult due to their overlapping features and yet has important life expectancy implications as well as vastly different genetic counseling requirements. Our patient presents with a mixed clinical picture. The desire for diagnostic certainty is not only to understand his prognosis but also to determine the risk to his siblings and assist in family planning. Based on the clinical overlap between the Hutchinson-Gilford progeria syndrome and mandibuloacral dysplasia, we analyzed the LMNA gene in this patient. When a heterozygous change was identified, the parents were analyzed for the mutation. Deoxyribonucleic acid analysis for the LMNA gene revealed a heterozygous G to A change at nucleotide 412 in exon 2 of the LMNA gene resulting in replacement of glutamic acid with lysine at codon 138 (412 G>A; glu138lys). Neither parent had a mutation. Our results show that codon 138 (412 G>A; glu138lys) is a newly identified mutation of LMNA gene that results in a progeroid syndrome which is phenotypically similar to mandibuloacral dysplasia.

Leukodystrophies are a broad class of genetic disorders that result in disruption or destruction of central myelination. Although the mechanisms underlying these disorders are heterogeneous, there are many common symptoms that affect patients irrespective of the genetic diagnosis. The comfort and quality of life of these children is a primary goal that can complement efforts directed at curative therapies. Contained within this report is a systems-based approach to management of complications that result from leukodystrophies. We discuss the initial evaluation, identification of common medical issues, and management options to establish a comprehensive, standardized care approach. We will also address clinical topics relevant to select leukodystrophies, such as gallbladder pathology and adrenal insufficiency. The recommendations within this review rely on existing studies and consensus opinions and underscore the need for future research on evidence-based outcomes to better treat the manifestations of this unique set of genetic disorders.

Cerebral creatine deficiency syndromes (CCDS) are a group of inborn errors of creatine metabolism that involve AGAT and GAMT for creatine biosynthesis disorders and SLC6A8 for creatine transporter (CT1) deficiency. Deficiencies in the three enzymes can be distinguished by intermediate metabolite levels, and a definitive diagnosis relies on the presence of deleterious mutations in the causative genes. Mutations and unclassified variants were identified in 41 unrelated patients, and 22 of these mutations were novel. Correlation of sequencing and biochemical data reveals that using plasma guanidinoacetate (GAA) as a biomarker has 100% specificity for both AGAT and GAMT deficiencies, but AGAT deficiency has decreased sensitivity in this assay. Furthermore, the urine creatine:creatinine ratio is an effective screening test with 100% specificity in males suspected of having creatine transporter deficiency. This test has a high false-positive rate due to dietary factors or dilute urine samples and lacks sensitivity in females. We conclude that biochemical screening for plasma GAA and measuring of the urine creatine:creatinine ratio should be performed for suspected CCDS patients prior to sequencing. Also, based on the results of this study, we feel that sequencing should only be considered if a patient has abnormal biochemical results on repeat testing.

Internal carotid artery pseudoaneurysm is an uncommon complication of retropharyngeal and parapharyngeal abscess in children. Treatment of the pseudoaneurysm has evolved in recent years from surgical ligation to endovascular techniques. Neurologic sequelae most commonly consist of Horner's syndrome with cerebral ischemia being uncommon. The clinical course of a 2-year-old boy with retropharyngeal abscess complicated by internal carotid artery pseudoaneurysm, is described and the literature is reviewed. A conventional angiogram confirmed the presence of a large pseudoaneurysm with no anterograde flow distal to the pseudoaneurysm and substantial collateral flow across the circle of Willis, with filling of the left anterior and middle cerebral arteries via the anterior and posterior communicating arteries. Endovascular occlusion resulted in nonfilling of the left internal carotid artery, pseudoaneurysm, and left internal jugular vein at the base of the skull. Following the procedure, the patient developed transient mild right hemiparesis associated with frontal lobe ischemia.

Recent advances in biochemical and molecular genetics have led to the discovery of new leukoencephalopathies. Despite these advances, many patients with leukoencephalopathy remain undiagnosed. A systematic approach to the investigation of these patients is needed to select the most appropriate testing strategy. In this article, the author presents a clinical and magnetic resonance imaging (MRI) based approach to the evaluation of patients with leukoencephalopathy.

Macrocephaly, enlarged head size, can be seen in a wide range of conditions including hydrocephalus and genetic syndromes. Benign familial macrocephaly may be seen in multiple generations and is not associated with neurologic concerns. When macrocephaly is seen in conjunction with abnormal white matter on neuroimaging, specific genetic leukoencephalopathies should be considered, including Alexander's disease, Canavan's disease, childhood ataxia with central hypomyelination/ vanishing white matter disease (CACH/VWMD), glutaric aciduria type I, L2-hydroxyglutaric aciduria, and megalencephalic leukoencephalopathy with subcortical cysts (MLC).

GM2-gangliosidosis, AB variant is a very rare form of GM2 gangliosidosis due to a deficiency of GM2 activator protein, associated with autosomal recessive mutations in GM2A. Less than ten patients, confirmed by molecular analysis, have been described in the literature.A 12-month-old Hmong girl presented to the neurometabolic clinic for evaluation of global developmental delay, hypotonia, and cherry red spots. The parents were not known to be consanguineous. Her examination was remarkable for hypotonia with hyperreflexia and excessive startling. The head circumference was normal. An extensive neurometabolic evaluation was negative.Developmental regression began at 14 months of age. Retinal examination at 16 months of age disclosed 4+ cherry red/black spots with "heaped up" ring of whitish infiltrate surrounding both foveae but no evidence of optic atrophy or peripheral retinal abnormalities. Repeat magnetic resonance imaging (MRI) scan at 17 months of age revealed delayed but interval myelination associated with abnormal signal intensity of the bilateral thalami presenting as T2 hyperintensity of the posterior thalami in the region of the pulvinar nuclei and T2 hypointensity in the anterior thalami. Sequencing of the GM2A gene revealed a homozygous c.160 G>T mutation, predicted to result in a premature protein termination p. Glu54*.

Alexander disease is a rare, progressive, and generally fatal neurological disorder that results from dominant mutations affecting the coding region ofGFAP, the gene encoding glial fibrillary acidic protein, the major intermediate filament protein of astrocytes in the CNS. A key step in pathogenesis appears to be the accumulation of GFAP within astrocytes to excessive levels. Studies using mouse models indicate that the severity of the phenotype correlates with the level of expression, and suppression of GFAP expression and/or accumulation is one strategy that is being pursued as a potential treatment. With the goal of identifying biomarkers that indirectly reflect the levels of GFAP in brain parenchyma, we have assayed GFAP levels in two body fluids in humans that are readily accessible as biopsy sites: CSF and blood. We find that GFAP levels are consistently elevated in the CSF of patients with Alexander disease, but only occasionally and modestly elevated in blood. These results provide the foundation for future studies that will explore whether GFAP levels can serve as a convenient means to monitor the progression of disease and the response to treatment.

Skin fibroblasts from patients with various fatty acid oxidation defects (FAOD) and four normal controls were subcultured in standard glucose-containing medium or in glucose-free medium simulating fasting. The FAOD fibroblasts developed microvesicular steatosis, which was greatly exacerbated in glucose-free medium. 'Rescue treatment' with glucose-containing medium was performed in the short-chain L-3-hydroxyacyl-CoA dehydrogenase-deficient (SCHADD) fibroblasts and resulted in a partial resolution of the steatosis and improved cellular viability. Transmission electron microscopy of autopsy specimens from the SCHADD patient demonstrated that most renal interstitial fibroblasts and approximately 50% of fibroblasts in the heart had microvesicular steatosis. The demonstration of microvesicular steatosis in parenchymal and/or cultured skin fibroblasts may provide important and cost-effective screening tools for the detection of genetic defects of fatty acid oxidation.

We describe two brothers with bilateral exudative retinopathy, intracranial calcifications, a sclerotic bony disorder, and normal intelligence. The younger brother also has osteopenia, mild splenomegaly, and pancytopenia. We review the literature with emphasis on the unique features of these patients.

A 17-year-old previously healthy young man sought neurologic evaluation for a 5-year history of progressive gait disturbance, urinary incontinence, and constipation. His symptoms began at age 12 with bilateral leg pain, stiffness, and clumsiness, which progressed to a scissoring gait with reliance on gait aids. His gait had greatly worsened in the 3 to 4 months before evaluation. Extensive previous evaluation, including lumbar puncture, electromyogram, infectious disease evaluation, alpha-fetoprotein analysis, metabolic studies (including very long chain fatty acids) and genetic testing for Friedrich ataxia, PLP-1, and spinocerebellar ataxia types 1, 2, 3, 6, 7, 8, 10, and 17, had been normal. His last neuroimaging had occurred 5 years before, with normal results for head and spine magnetic resonance imaging (MRI). His physical examination revealed mildly decreased leg adductor and flexor strength, a spastic gait, and a positive Romberg sign. His lower extremity deep tendon reflexes were hyperactive with sustained ankle clonus bilaterally. His light touch sense was markedly reduced in both lower extremities, with mildly reduced vibrational sense. The rest of his neurologic examination, including upper extremity tone and deep tendon reflexes, was normal. He was also found to have neurogenic bowel and bladder. Nerve conduction studies were normal, and needle examination revealed poor relaxation consistent with spasticity but no evidence of peripheral neuropathy. Somatosensory evoked potentials revealed a conduction block in the central proprioceptive pathways serving the lower extremities. A thermoregulatory sweat test revealed anhidrosis of the bilateral lower extremities.

Background Iron deficiency is the most common nutritional deficiency in children. It affects 9% of children ages 1-3 years. Iron is essential for effective mitochondrial electron transport and neurotransmitter synthesis. Iron deficiency has been correlated with impaired psychomotor development, pica, attention deficit disorder, periodic limb movements of sleep, and breath-holding spells. Ferritin is the storage form of iron. Patient Series We assessed three children referred for developmental concerns. Extensive testing and neuroimaging were all unremarkable except for low iron stores. Dietary histories revealed excessive milk consumption in two of the children. After dietary adjustments and iron supplementation, iron stores normalized. Conclusions This cohort demonstrated a dramatic improvement in cognition once iron stores were repleted, suggesting iron studies should be considered as part of initial investigations of patients with cognitive concerns.

X-linked adrenoleukodystrophy, a peroxisomal disorder, is the most prevalent inherited leukodystrophy. Boys with the childhood cerebral form of the disease present with progressive neurological dysfunction, visual loss and adrenal insufficiency. Stem cell transplantation arrests the neurological progression of the disease when performed early. The multidisciplinary clinical and stem cell transplantation program developed at the Mayo Clinic is described.

Importance Reports of pediatric-onset stiff-man syndrome (SMS) are rare. This may be an underrecognized disorder in child neurology practice. Objective To describe patients with disorders in the SMS spectrum beginning in childhood. Design, Setting, and Participants This study was a medical record review and serological evaluation conducted at child and adult neurology clinics at the Mayo Clinic, Rochester, Minnesota. Systematic review of the literature was conducted of patients who presented from 1984-2012 with onset of symptomatic SMS occurring at age 18 years or younger. Main Outcomes and Measures Response to symptomatic and immunotherapies, patient and physician reported, including modified Rankin scale. Results We identified 8 patients with childhood-onset SMS, representing 5% of patients with SMS evaluated at Mayo Clinic during a period of 29 years (4 were girls). The median age at symptom onset was 11 years (range, 1-14 years). The diagnosis in 3 patients was not established until adulthood (median symptom duration at diagnosis, 14 years; range, 0-46 years). The phenotypes encountered were: classic SMS (n = 5, involving the low back and lower extremities), variant SMS (n = 2, limited to 1 limb [with dystonic posture] or back), and progressive encephalomyelitis with rigidity and myoclonus (n = 1). Initial misdiagnoses included functional movement disorder (n = 2), generalized dystonia and parkinsonism (n = 1), and hereditary spastic paraparesis (n = 1). Six patients had 1 or more coexisting autoimmune disorders: type 1 diabetes mellitus (n = 4), thyroid disease (n = 2), and vitiligo (n = 2). Serologic study results revealed glutamic acid decarboxylase 65–IgG in all cases (median value, 754 nmol/L; range, 0.06-3847 nmol/L; normal value, ≤0.02 nmol/L) and glycine receptor antibody in 3 cases. Improvements were noted with symptomatic therapy (diazepam, 6 of 6 patients treated, and oral baclofen, 3 of 3 treated) and immunotherapy (intravenous immune globulin, 3 of 4 treated and plasmapheresis, 3 of 4 treated). The 3 patients with glycine receptor antibody all improved with immunotherapy. At last follow-up, 4 patients had mild or no symptoms, but 4 had moderate or severe residual symptoms and required maintenance symptomatic therapy (n = 5) and immunotherapy (n = 4). Ten of 12 pediatric SMS cases identified by literature review had a severe whole-body phenotype resembling progressive encephalomyelitis with rigidity and myoclonus. Conclusions and Relevance Childhood-onset SMS is a rare but underrecognized and treatable disorder. Serological and electrophysiological testing aid diagnosis.

We collected data on 48 patients from 38 families with guanidinoacetate methyltransferase (GAMT) deficiency. Global developmental delay/intellectual disability (DD/ID) with speech/language delay and behavioral problems as the most affected domains was present in 44 participants, with additional epilepsy present in 35 and movement disorder in 13. Treatment regimens included various combinations/dosages of creatine-monohydrate, L-ornithine, sodium benzoate and protein/arginine restricted diets. The median age at treatment initiation was 25.5 and 39 months in patients with mild and moderate DD/ID, respectively, and 11 years in patients with severe DD/ID. Increase of cerebral creatine and decrease of plasma/CSF guanidinoacetate levels were achieved by supplementation with creatine-monohydrate combined with high dosages of t-ornithine and/or an arginine-restricted diet (250 mg/kg/d L-arginine). Therapy was associated with improvement or stabilization of symptoms in all of the symptomatic cases. The 4 patients treated younger than 9 months had normal or almost normal developmental outcomes. One with inconsistent compliance had a borderline IQ at age 8.6 years. An observational GAMT database will be essential to identify the best treatment to reduce plasma guanidinoacetate levels and improve long-term outcomes. (C) 2013 The Authors. Published by Elsevier Inc. All rights reserved.

The understanding of the genetic basis of late-onset leukoencephalopathies has continued to increase in recent years. The most commonly presenting leukoencephalopathies in adulthood can be late-onset manifestations of metabolic pathways. The understanding of these diagnoses is crucial to the evaluation of adult patients presenting with leukoencephalopathies. The authors provide an overview of the common leukoencephalopathies in adulthood, the current understanding of the pathology, and genetics of these disorders with typical imaging findings. When available, treatment options will be discussed.

Metachromatic leukodystrophy and Krabbe's disease are among the most widely recognized causes of leukodystrophy. However, white matter changes have been described in several other lysosomal storage disorders. These conditions are summarized and those associated with hypomyelination are reviewed in more detail.

A 20-year-old woman was referred to our CNS demyelinating disease clinic for assessment of seizures, cognitive decline and multifocal CNS disease. The patient had a history of seizures and leukoencephalopathy of undetermined etiology. She recently experienced worsening of clinical symptoms with progressive cognitive impairment and imbalance. She had been advised to reduce the dose of her anti-epileptic medications for concern about drug toxicity as the etiology. After reducing the antiepileptic dosage she developed status epilepticus requiring intubation and medication-induced coma for approximately 48 h. She recovered without further clinical or electrographic seizures, and she was referred to our clinic. The family reported cognitive and behavioral changes, for approximately 1 year prior to the current presentation. She had had gradually increasing difficulty with memory, frequent word-finding problems, and a reduced attention span. They described she required frequent repetition of even simple instructions. The family also noted flattened affect, describing her as apathetic and disengaged. Further

Autoimmunity targeting voltage-gated potassium channel complexes have not been systematically documented in children. Identified in the Neuroimmunology Laboratory records of Mayo Clinic were 12 seropositive children, 7 among 252 Mayo Clinic pediatric patients tested on a service basis for serologic evidence of neurologic autoimmunity (June 2008-April 2010), 4 during the assay's preimplementation validation (before June 2008) and 1 non-Mayo patient with available clinical information. Neurologic manifestations were subacute and multifocal. Three had global developmental regression, 6 movement disorders, 4 dysarthria, 3 seizures, 1 Satoyoshi syndrome, 1 painful red feet, 2 insomnia, 2 gastrointestinal dysmotility, and 2 small fiber neuropathy. Neoplasia was found in 1 child. Treating physicians recorded improvement in all 7 children who received immunotherapy. Neurologic symptom relapse occurred in 3 of 6 children after ceasing immunotherapy. These findings highlight a diverse clinical spectrum of neuronal potassium channel complex autoimmunity in children, and they illustrate benefit from early initiated immunotherapy, with a tendency to relapse when therapy ceases. Diagnosis is generally delayed in the process of eliminating neurodegenerative causes. Currently 2.7% of pediatric sera evaluated for neurologic autoimmunity are positive for neuronal potassium channel complex-reactive immunoglobulin G. The frequency and full spectrum of neurologic accompaniments remains to be determined.