Survey of patients with spinal muscular atrophy on the island of Shikoku, Japan.

BACKGROUND: Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder associated with spinal motor neuron loss and characterized by generalized muscle weakness. Only a few reports exist on SMA epidemiology in Japan. Additionally, nusinersen recently became available as a treatment for this condition. We estimated the prevalence of each type of SMA on Shikoku, Japan's fourth-largest major island. METHODS: We sent a questionnaire to all 131 hospitals in Shikoku that have pediatrics or neurology departments from March to September 2019, asking whether each hospital had SMA patients at that time. If so, we sent a second questionnaire to obtain more detailed information on the clinical data and treatment of each patient. RESULTS: A total of 117 hospitals (89.3%) responded to our first questionnaire, and 21 SMA patients were reported, 16 of whom had homozygous deletion of SMN1. Of the 21, nine had SMA type 1, five were type 2, five were type 3, one was type 4, and one was unidentified. The estimated prevalence for all instances of SMA and 5q-SMA was 0.56 and 0.43 per 100,000 people, respectively. Thirteen patients had received nusinersen therapy. Its outcomes varied from no obvious effects and being unable to sit to being able to sit independently. CONCLUSION: Our data showed the prevalence of SMA types 2 and 3 was relatively low on Shikoku compared with previous reports from other countries, suggesting delayed diagnosis may affect the results. Remaining motor function may be one predicting factor. Greater awareness of SMA among clinicians and patients seems necessary for more accurate epidemiological studies.

Milder forms of muscular dystrophy associated with POMGNT2 mutations.

OBJECTIVE: To determine the genetic variants in patients with dystroglycanopathy (DGP) and assess the pathogenicity of these variants. METHODS: A total of 20 patients with DGP were identified by immunohistochemistry or Western blot analysis. Whole-exome sequencing (WES) was performed using patient samples. The pathogenicity of the variants identified was evaluated on the basis of the phenotypic recovery in a knockout (KO) haploid human cell line by transfection with mutated POMGNT2 cDNA and on the basis of the in vitro enzymatic activity of mutated proteins. RESULTS: WES identified homozygous and compound heterozygous missense variants in POMGNT2 in 3 patients with the milder limb-girdle muscular dystrophy (LGMD) and intellectual disability without brain malformation. The 2 identified variants were located in the putative glycosyltransferase domain of POMGNT2, which affected its enzymatic activity. Mutated POMGNT2 cDNAs failed to rescue the phenotype of POMGNT2-KO cells. CONCLUSIONS: Novel variants in POMGNT2 are associated with milder forms of LGMD. The findings of this study expand the clinical and pathologic spectrum of DGP associated with POMGNT2 variants from the severest Walker-Warburg syndrome to the mildest LGMD phenotypes. The simple method to verify pathogenesis of variants may allow researchers to evaluate any variants present in all of the known causative genes and the variants in novel candidate genes to detect DGPs, particularly without using patients' specimens.

Hypoalbuminemia in early onset dentatorubral-pallidoluysian atrophy due to leakage of albumin in multiple organs.

We delineate a complication of hypoalbuminemia in dentatorubral-pallidoluysian atrophy (DRPLA), which we have found to be common in this disorder. In addition, we explored the pathogenesis of this phenomenon through clinical and histological examinations. Clinical course and laboratory findings of nine patients with childhood-onset DRPLA (aged 6-49 years; CAG repeat length 62-93) were retrospectively reviewed. Autopsied specimens from three patients were examined by histopathological and immunohistochemical analyses. Eight DRPLA patients showed hypoalbuminemia <3.5 g/dl in the initial stages of the disease (age, 2-32 years), which correlated with the CAG repeat length in each patient. Disease worsened in six patients, often triggered by febrile infections and accompanied by increased urinary protein excretion. One patient showed increased fecal α1-antitripsin while another showed accumulation of radioactive albumin in the urinary and gastrointestinal tracts after intravenous infusion. Immunohistochemistry revealed albumin-containing monocytes and astrocytes in the perivascular areas of the cerebral white matter. Fluid collection in the glomerular capillaries was noted. Immunolabeling using antibodies against the expanded polyglutamine (polyQ) polypeptide was positive in cerebral cortical neurons, hepatocytes, renal collecting ducts, and glomerular podocytes, which act as filtration barrier against serum proteins. Serum albumin appears to easily leak from blood vessels in certain visceral organs in DRPLA during later stages of the illness, particularly in the kidneys of patients with largely expanded CAG repeats. We hypothesize that the accumulation of the DRPLA gene product with expanded polyQ sequences in the podocytes results in the dysfunction of the glomerular filtration barrier.

Progressive diffuse brain atrophy in West syndrome with marked hypomyelination due to SPTAN1 gene mutation.

A 1-year-old male began suffering from West syndrome at 3 months of age, when electroencephalography revealed hypsarrhythmia accompanied by a periodic, brief suppression phase. The administration of adrenocorticotropic hormone was partially effective for stopping the condition, and the seizure type evolved into brief tonic seizures at 6 months. Thereafter, progressive atrophy of the brain became evident by 9 months of age, predominantly at the brainstem and cerebellum. Severe hypomyelination of the cerebral white matter was revealed at the age of 1 year, and a de novo heterozygous mutation in the SPTAN1 gene was confirmed. The patient showed severely impaired psychomotor development, and had gained no visual attention. These findings contribute to the characterization of this recently established entity and facilitate the identification of further patients.

[Clinical aspects of epilepsy in children with periventricular leukomalacia].

UNLABELLED: We investigated the frequency and characteristics of epilepsy in 63 children (39 males and 24 females) with cerebral palsy caused by periventricular leukomalacia, who were born preterm at <34 weeks' gestation and followed for more than five years (duration: 5-18 years, mean: 9.6 years). While seven (11%) of the 63 patients had febrile convulsions (FC), 11 (17%) were associated with symptomatic localization-related epilepsy (SLRE) and 8 (13%) with West syndrome (WS). The gestational ages of the WS group were significantly (p<0.05) longer than in FC group. The DQ of the SLRE and WS groups were significantly (p<0.01) lower than in the N-S group. The frequency of spastic quadriplegia was 19%, 29%, 36%, 50% in the N-S, FC, SLRE, WS groups, respectively. Among the 11 SLER patients, 5 had one seizure type, while 3 had two and 3 had three seizure types. The seizure patterns included complex partial seizures (CPS) in 8, secondarily generalized partial epileptic seizures in 8, and simple partial seizures in 4. One patients in the WS group developed CPS, and another patient developed epilepsy undetermined after infancy. Regarding the main localizing symptoms of SLRE, oculogyric seizures were observed in 7 patients and hemi-facial seizures were observed in 8 patients. In all WS patients, the location of the epileptiform discharges was in the parieto-occipital area, while 8 of 11 patients with SLES had it in the central area. IN CONCLUSION: 30% of all patients with PVL were associated with epilepsy. WS developed in 13% during early infancy and SLRE developed in 17% after infancy. The most common epileptic seizure in the patients with PVL was complex partial seizure.