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 l-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.
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 PARTICIPANTSThis 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 MEASURESResponse to symptomatic and immunotherapies, patient and physician reported, including modified Rankin scale. RESULTSWe 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, Յ0.02 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.
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.
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.
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.
RESPONSE TO IMMUNOTHERAPY IN A 20-MONTH-OLD BOY WITH ANTI-NMDA RECEPTOR ENCEPHALITISEncephalitis associated with antibodies against the NMDA receptor (anti-NMDA-R) is characterized by prominent psychiatric symptoms, dyskinesias, seizures, autonomic instability, and central hypoventilation. 1 We report a 20-month-old boy with oralbuccal dyskinesia, choreoathetosis, seizures, and encephalopathy, consistent with anti-NMDA-R encephalitis.Level of evidence. This report is Class IV evidence and is a single observational study without controls. Case report.A 20-month-old boy had a pruritic maculopapular rash over his face, trunk, and arms for 2 weeks without preceding fever or illness. A week later, he developed involuntary tongue thrusting and right hand twitching. He spoke less and became less interactive. On admission, his temperature was 39.2 o C. Examination showed oral-buccal dyskinesia and choreoathetosis, particularly the upper extremities (video on the Neurology ® Web site at www. neurology.org). Complete blood count showed a white cell count of 15.6 ϫ 10 9 /L with neutrophilic predominance. CSF revealed slightly elevated total nucleated cells of 5/L with lymphocytic predominance (65%), normal protein (24 mg/dL), glucose (59 mg/dL), and lactate (1 mmol/L) concentrations. Nasogastric tube was placed owing to impaired oropharyngeal coordination. Prolonged video EEG recorded several generalized seizures from sleep. There was no electrographic correlate with the involuntary movements, which persisted during wakefulness and sleep. Brain MRI and magnetic resonance spectroscopy on day 2 were normal.Bacterial cultures in the blood, urine, and CSF were negative. Serologies and PCRs in the serum and CSF were negative for infectious etiology (table e-1). Investigations for inborn errors of metabolism and toxins were unrevealing. Antistreptolysin O, anti-DNAse, peripheral blood smear, vitamin E, copper, ceruloplasmin, homovanillic acid, vanillylmandelic acid, thyroid peroxidase antibody, and CSF neuro-
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