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Objective: Mitochondrial DNA polymerase γ (POLG1) mutations in children often manifest as Alpers syndrome, whereas in adults, a common manifestation is mitochondrial recessive ataxia syndrome (MIRAS) with severe epilepsy. Because some patients with MIRAS have presented with ataxia or epilepsy already in childhood, we searched for POLG1 mutations in neurologic manifestations in childhood. Methods: We investigated POLG1 in 136 children, all clinically suspected to have mitochondrial disease, with one or more of the following: ataxia, axonal neuropathy, severe epilepsy without known epilepsy syndrome, epileptic encephalopathy, encephalohepatopathy, or neuropathologically verified Alpers syndrome. Results: Seven patients had POLG1 mutations, and all of them had severe encephalopathy with intractable epilepsy. Four patients had died after exposure to sodium valproate. Brain MRI showed parieto-occipital or thalamic hyperintense lesions, white matter abnormality, and atrophy. Muscle histology and mitochondrial biochemistry results were normal in all. Conclusions: POLG1 analysis should belong to the first-line DNA diagnostic tests for children with an encephalitis-like presentation evolving into epileptic encephalopathy with liver involvement (Alpers syndrome), even if brain MRI and morphology, respiratory chain activities, and the amount of mitochondrial DNA in the skeletal muscle are normal. POLG1 analysis should precede valproate therapy in pediatric patients with a typical phenotype. However, POLG1 is not a common cause of isolated epilepsy or ataxia in childhood.

BACKGROUND: Extensive cerebral calcifications and leukoencephalopathy have been reported in two rare disorders Coats plus and leukoencephalopathy with calcifications and cysts. In the latter, a progressive formation of parenchymal brain cysts is a special feature, whereas Coats plus is characterized by intrauterine growth retardation, bilateral retinal telangiectasias and exudations (Coats disease), sparse hair, and dysplastic nails without cyst formation. METHODS: We identified 13 patients, including two pairs of siblings, with extensive cerebral calcifications and leukoencephalopathy. We reviewed clinical, ophthalmologic, radiologic and neuropathologic data of seven deceased patients and studied five patients prospectively. RESULTS: Eleven patients were small for gestational age; the other symptoms emerged from infancy to adolescence. All patients had neurologic symptoms including seizures, spasticity, dystonia, ataxia, and cognitive decline. Progressive intracerebral calcifications involved deep gray nuclei, brainstem, cerebral and cerebellar white matter, and dentate nuclei and were accompanied by diffuse white matter signal changes and, in five patients, cerebral cysts. Eleven patients had retinal telangiectasias or angiomas. Additional features were skeletal and hematologic abnormalities, intestinal bleeding, and poor growth. Neuropathologic examination showed extensive calcinosis and abnormal small vessels with thickened, hyalinized wall and reduced lumen. CONCLUSIONS: Our data suggest that Coats plus syndrome and leukoencephalopathy with calcifications and cysts belong to the same spectrum. The primary abnormality seems to be an obliterative cerebral angiopathy involving small vessels, leading to dystrophic calcifications via slow necrosis and finally to formation of cysts and secondary white matter abnormalities.

Pitt-Hopkins syndrome is a rare dysmorphic mental retardation syndrome marked by daytime spells of overbreathing interrupted by apnoea. The dysmorphism consists of a large beaked nose, cup-shaped ears with broad helices, a wide mouth, Cupid's bow upper lip, wide and shallow palate and broad or clubbed fingertips. The four patients described so far have been sporadic and represented both sexes. In addition, a pair of sibs with atypical features has been reported as possible Pitt-Hopkins syndrome cases. We describe two unrelated Pitt-Hopkins syndrome patients in order to further define the phenotype. In addition to severe developmental retardation, hypotonia, postnatal growth retardation, microcephaly, abnormal breathing and characteristic dysmorphic features, both had epilepsy and intestinal problems with severe constipation in one and Hirschsprung disease in the other. Other abnormalities were hypopigmented skin macules in one and high-grade myopia in the other. Both had unusual frontal slow-and-sharp-wave discharges on electroencephalography. Magnetic resonance imaging in both showed a similar hypoplastic corpus callosum with missing rostrum and posterior part of the splenium and bulbous caudate nuclei bulging towards the frontal horns. Chromosomal analysis and subtelomere fluorescence in-situ hybridization studies were normal. No mutations were found in the MECP2 or ZFHX1B genes. Extensive metabolic and mitochondrial screens were normal. The electroencephalography and brain magnetic resonance imaging findings appear to be further diagnostic signs in Pitt-Hopkins syndrome, which is also one of the syndromes associated with Hirschsprung disease.

Background: A new leukoencephalopathy with brainstem and spinal cord involvement and high brain lactate was recently defined. The authors describe five new patients with this entity. Methods: Brain MRI was performed in all patients and spinal MRI and proton magnetic resonance spectroscopy ( 1 H-MRS) in four patients. Laboratory examinations ruled out classic leukodystrophies. Results: MRI showed signal abnormalities in the periventricular and deep white matter, in the pyramidal tracts, mesencephalic trigeminal tracts, in the cerebellar connections, and in dorsal columns of the spinal cord. MRS showed decreased N -acetylaspartate and increased lactate in the white matter of all patients. In one patient choline-containing compounds were elevated. A slowly progressive sensory ataxia and tremor manifested at the age of 3 to 16 years and distal spasticity in adolescence. One 13-year-old patient was asymptomatic. Conclusions: A slowly progressive sensory ataxia is a typical feature in this new leukodystrophy. MRS favors a primary axonal degeneration.

We report three unrelated patients with hypertrichosis, mild to moderate mental retardation, and dysmorphic facial features including low anterior hairline, thick arched eyebrows, nose with broad tip and columella below alae nasi, short philtrum, thick drooping lower lip and simple posteriorly rotated ears. They also had rough skin with hyperkeratotic plaques. Feet and finger tips were broad. All of them had personality problems like aggressiveness, stubborn temperament or tendency to withdraw. Brain MRI showed thick and short corpus callosum. We believe that these patients represent a new syndrome of unknown aetiology.

The authors reorganized the emergency room (ER) by moving CT to the ER and streamlining triage by prenotification by emergency medical services (EMS), which reduced in-hospital delays and enhanced access to stroke thrombolysis. CT delay dropped from 1 hour 3 minutes +/- 14 minutes in 1999 to 7 +/- 2 minutes in 2004 (p0.0001). Door-to-needle time dropped from 1 hour 28 minutes +/- 7 minutes to 50 +/- 3 minutes (p0.001), while symptom-to-needle time dropped from 2 hours 44 minutes +/- 6 minutes to 2 hours 5 minutes +/- 4 minutes (p0.0001). From 23 patients in 1999, thrombolysis access was increased to 100 patients in 2004 and 183 patients in 2005.

Autosomal dominant progressive external ophthalmoplegia (adPEO) is a mitochondrial disease characterized by accumulation of multiple large deletions of mtDNA in patients9 tissues. We previously showed that the disease is genetically heterogeneous by assigning two nuclear loci predisposing to mtDNA deletions: one on chromosome 10q 23.3–24.3 in a Finnish family and one on 3p 14.1–21.2 in three Italian families. To reveal any locus-specific disease features, we report here the clinical, biochemical, and molecular genetic characteristics of the 10q-linked disease in the single family reported to date. All seven patients and four asymptomatic subjects had ragged-red fibers and multiple deletions of mtDNA in their muscle. Ptosis and external ophthalmoplegia were the major clinical findings, and depression or avoidant personality traits were frequently, but not consistently, present in the subjects carrying mutant mtDNA. In six of the subjects with mutant mtDNA, the activities of the respiratory chain complexes I or IV, or both, were below or within the low normal range. Two autopsy studies revealed the characteristic distribution of mutant mtDNA in these patients: highest proportion of mutant mtDNA is found in different parts of the brain, followed by the skeletal and ocular muscle, and the heart.

We studied 88 patients with acute encephalitis using hexamethylpropyleneamine oxime and single photon emission computed tomography (SPECT). All patients had been initially treated with intravenous acyclovir. The etiology could be disclosed in 37 patients (42%), which included 15 patients with herpes simplex encephalitis, 7 with varicella-zoster encephalitis, and 29 with other encephalitides (Mycoplasma, adenovirus, influenza, rotavirus, rubella, Epstein-Barr, arbovirus, syphilis, and tuberculosis). Unilateral hyperperfusion in SPECT was an independent predictor of poor prognosis, whereas neither clinical outcome variables, such as seizures, state of consciousness, and focal neurologic findings, nor CSF or EEG findings were not. Focal unilateral hyperperfusion is an indicator of severe inflammation of the brain tissue and predicts a poor outcome as assessed in terms of activities of daily living after recovery.

We evaluated the effect of spinal cord abnormalities on lower urinary tract function in patients with anorectal abnormalities.We examined 30 patients with anorectal anomalies mainly because of fecal or urinary incontinence. All patients underwent spinal magnetic resonance imaging and urodynamic investigation.Major lumbosacral abnormalities were detected in 57% of patients, including 13, 4 and 3 with a tethered cord, syringomyelia and caudal regression, respectively. Significant dysfunction of the lower urinary tract in 57% of the cases involved an overactive detrusor in 11, detrusor-sphincter dyssynergia in 4, distended bladder in 4 and lazy bladder in 1. When the spinal cord was normal, 54% of the patients had abnormal urodynamic findings but when the spinal cord was abnormal, 59% had abnormal urodynamics. When the bony spine was normal, 33% of the patients had an abnormal spinal cord but when the bony spine was abnormal, 69% had an abnormal spinal cord.Patients with anorectal abnormalities and fecal or urinary incontinence problems often have an abnormal spinal cord and abnormal urodynamic findings. However, the state of the spinal cord is not the only factor explaining lower urinary tract function. Thus, the possibility of lower urinary tract dysfunction should be considered in each patient with anorectal abnormalities. If the patient has symptoms or findings suggesting abnormal lower urinary tract function urodynamic evaluation should be performed.