Treatment of ZC4H2 Variant-Associated Spastic Paraplegia with Selective Dorsal Rhizotomy and Intensive Postoperative Rehabilitation: A Case Report.

Selective dorsal rhizotomy (SDR) has been used to treat children with spastic cerebral palsy (CP), and its beneficial effect on quality of life and ambulation has been confirmed in long-term follow-up studies. However, the role of SDR in the treatment of spasticity in patients with hereditary spastic paraplegia (HSP) and related disorders is not well-established. Here, we report the first patient with the ZC4H2 variant who underwent SDR to treat spastic paraplegia. Abnormal gait was discovered during a regular checkup at the age of 3 years and 9 months, and she was diagnosed with spastic paraplegia. She was heterozygous for the ZC4H2 variant and underwent SDR at the age of 5 years and 11 months, which alleviated the spasticity. The patient underwent inpatient postoperative rehabilitation for 4 months and continued outpatient physiotherapy after discharge. The Gross Motor Function Measure-88 score and maximum walking speed decreased transiently 1 month postoperatively, but gradually recovered, and continuously improved 6 months postoperatively. SDR and postoperative intensive rehabilitation were effective in improving motor and walking functions up to 6 months after surgery, although long-term follow-up is needed to draw conclusions.

The Clinical Course and Treatment of a Case of Refractory Systemic Juvenile Myasthenia Gravis Successfully Treated with Thymectomy.

Juvenile myasthenia gravis (JMG) exhibits a more favorable response to glucocorticoids and has a better prognosis than adult myasthenia gravis. However, no established treatment exists for refractory JMG. Although thymectomy has been performed in several patients with refractory systemic JMG, there are few detailed clinical descriptions of patients who underwent thymectomy. Here, we present the case of a 10-year-old boy with refractory systemic JMG who was successfully treated with thymectomy. The patient developed symptoms, including dysphagia, malaise, diurnal ptosis, and weakness in the trunk muscles, and he was diagnosed with generalized JMG. Despite undergoing various treatments, including steroids, tacrolimus, steroid pulse therapy, intravenous immunoglobulin, azathioprine (AZT), and rituximab, his symptoms did not improve. Therefore, he underwent a thoracoscopic thymectomy 24 months after disease onset. Thymectomy led to remission, as demonstrated by a significant reduction in the quantitative myasthenia gravis score and anti-acetylcholine receptor antibody levels, which persisted for 43 months after surgery. Our case demonstrates the effectiveness of thymectomy in systemic JMG patients with positive anti-acetylcholine receptor antibodies, despite therapeutic failure with AZT and rituximab, within 2 years of disease onset.

Two Siblings with Cerebellar Ataxia, Mental Retardation, and Disequilibrium Syndrome 4 and a Novel Variant of ATP8A2.

Cerebellar ataxia, mental retardation, and disequilibrium syndrome 4 (CAMRQ4) is early onset neuromotor disorder and intellectual disabilities caused by variants of ATP8A2. We report sibling cases and systematically analyze previous literature to increase our understanding of CAMRQ4. Japanese siblings presented with athetotic movements at 1 and 2 months of age. They also had ptosis, ophthalmoplegia, feeding difficulty, hypotonia, and severely delayed development. One patient had retinal degeneration and optic atrophy. Flattening of the auditory brainstem responses and areflexia developed. At the last follow-up, neither patient could sit or achieve head control, although some nonverbal communication was preserved. Whole exome sequencing revealed compound heterozygous variants of ATP8A2: NM_016529.6:c.[1741C>T];[2158C>T] p.[(Arg581*)];[(Arg720*)]. The p.(Arg581*) variant has been reported, while the variant p.(Arg720*) was novel. The symptoms did not progress in the early period of development, which makes it difficult to distinguish from dyskinetic cerebral palsy, particularly in solitary cases. However, visual and hearing impairments associated with involuntary movements and severe developmental delay may be a clue to suspect CAMRQ4.

A patient with early-onset SMAX3 and a novel variant of ATP7A.

OBJECTIVE: To describe clinical and genetic studies on a patient with early-onset spinal muscular atrophyX3 (SMAX3) with novel variant of ATP7A. METHODS: Clinical, neurophysiological, neuroimaging and pathological examinations were performed. Whole exome sequencing was applied to search genetic bases of this patient. RESULTS: The patient had gait abnormality from early infantile period. Muscle imaging at 42 years old showed predominant involvement of proximal muscles as compared to the distal muscles. The patient had a novel variant of ATP7A, which was the fourth genotype of ATP7A exhibited as SMAX3. Contrary to previous reports of distal motor neuropathy, the clinical and neuroimaging findings in this case revealed dominant involvement in the proximal portion of the extremities and trunk, which is similar to patients with type III SMA. CONCLUSION: The dominant involvement of proximal motor system in this patient may expand the phenotypic variability of SMAX3. We need to be aware of this disorder in differential diagnosis of patients with type III SMA-like phenotype.

Two males with sick sinus syndrome in a family with 0.6 kb deletions involving major domains in MECP2.

Mutations in methyl-CpG-binding protein 2 (MECP2) in males can lead to various phenotypes, ranging from neonatal encephalopathy to intellectual disability. In this study, using Nord's method of next-generation sequencing in three siblings, we identified a 0.6 kb deletion involving the transcriptional repression domain (TRD). Two males and one female had intellectual disability and apnea, but none met the criteria of Rett syndrome. Both males had sick sinus syndrome and severe tracheomalacia that resulted in early death. The mother, with skewed X-inactivation, had no symptoms. Therefore, this mutation is pathological for both males and females, resulting in sick sinus syndrome and severe tracheomalacia with strong reproducibility in males. Deletions involving major domains in MECP2 can result in a severe phenotype, and deletion of the TRD domain can cause severe autonomic nervous system dysregulation in males in these cases.

Leucine-485 deletion variant of BRAF may exhibit the severe end of the clinical spectrum of CFC syndrome.

The genotype-phenotype correlation in BRAF variant in cardio-facio-cutaneous (CFC) syndrome is not clearly defined. Here we report a case with a severe clinical phenotype and a novel BRAF variant, p.Leu485del. The present case showed severe intellectual disability, impaired awareness, hyperekplexia, involuntary movements, early onset refractory seizures, and delayed myelination on brain magnetic resonance imaging as well as a polycystic and dysplastic kidney, which are previously unreported anomalies in CFC or RAS/mitogen-activated protein kinase syndromes related to BRAF variant. CFC syndrome, especially caused by BRAF variant, should be included in the differential diagnosis of patients with developmental and epileptic encephalopathies and hyperekplexia. Furthermore, we need to keep in mind that missense variants or the deletion of Leucine-485 may be associated with severe symptoms.

A case of new PCDH12 gene variants presented as dyskinetic cerebral palsy with epilepsy.

Here we report a Japanese patient with new compound heterozygous truncating variants in the PCDH12 gene. As compared to the previously reported families who had congenital microcephaly, intrauterine growth retardation, intracranial calcification, and neonatal seizure associated with dysplasia of the midbrain-hypothalamus-optic tract, the present patient showed no midbrain-hypothalamus dysplasia or congenital/postnatal microcephaly, but dyskinetic cerebral palsy and severe intellectual disability as well as multifocal epilepsy. To understand phenotypic spectrum associated with PCDH12 variants, more reports are needed.

Neuroepidemiology of Porencephaly, Schizencephaly, and Hydranencephaly in Miyagi Prefecture, Japan.

BACKGROUND: No population-based surveys of porencephaly, schizencephaly, and hydranencephaly have been conducted in Japan or other Asian countries. We performed a neuroepidemiologic analysis to elucidate the incidence of porencephaly, schizencephaly, and hydranencephaly in Miyagi prefecture, Japan, during 2007-2011. METHODS: We sent inquiry forms in February 2012 to three neonatal intensive care units, 25 divisions of orthopedic surgery in municipal hospitals, 33 divisions of pediatrics including one university hospital, municipal hospitals, pediatric practitioners, and institutions for physically handicapped children located in Miyagi prefecture. These covered all clinics related to pediatric neurology and orthopedic surgery in Miyagi prefecture. In the inquiry, diagnostic criteria for porencephaly, schizencephaly, and hydranencephaly were described and representative images of magnetic resonance imaging were shown. We obtained an 82% (27 of 33) response rate from the divisions of pediatrics, a 100% (3 of 3) response rate from the neonatal intensive care units, and a 68% (17 of 25) response rate from orthopedic surgery clinics. The magnetic resonance imaging scans of each patient were retrieved and inspected. RESULTS: Five, one, and two individuals developed porencephaly, schizencephaly, and hydranencephaly, respectively. The estimated incidence rates of porencephaly, schizencephaly, and hydranencephaly were 5.2 (95% confidence interval [CI], 0.6-9.8), 1.0 (95% CI, 0.0-3.1), and 2.1 (95% CI, 0.0-5.0) per 100,000 live births, respectively. CONCLUSIONS: The prevalence rates of porencephaly, schizencephaly, and hydranencephaly at birth reported herein are compatible with results reported previously in the United States and European countries. The overall prevalence rate of these three diseases was 8.3 (95% CI, 2.6-14.1) per 100,000 live births.