Clinical and mutational spectrum of Japanese patients with recessive variants in SH3TC2.

SH3TC2, known as the causative gene of autosomal recessive demyelinating Charcot-Marie-Tooth type 4C (CMT4C), was also found linked to a mild mononeuropathy of the median nerve with an autosomal dominant inheritance pattern. Using DNA microarray, Illumina MiSeq, and Ion proton, we carried out gene panel sequencing among 1483 Japanese CMT patients, containing 397 patients with demyelinating CMT. From seven patients with demyelinating CMT, we identified eight recessive variants in the SH3TC2 gene, consisting of five novel (pathogenic/likely pathogenic) and three reported variants. Additionally, from two patients with axonal CMT, we detected a reported recessive variant, p.Arg77Trp, which was herein reclassified as variant with unknown significance. Of the seven CMT4C patients (six females and one male), 2/7 patients developed symptoms at their first decade, and 5/7 patients lost their ambulation around age 50. Scoliosis was observed from more than half (4/7) of these patients, whereas hearing loss is the most common symptom of central nervous system (6/7). No median nerve mononeuropathy was recorded from their family members. We identified recessive variants in SH3TC2 from 1.76% of demyelinating CMT patients. An uncommon gender difference was recognized and the wild spectrum of these variants suggests mutational diversity of SH3TC2 in Japan.

Novel mutations in SH3TC2 in a young Japanese girl with Charcot-Marie-Tooth disease type 4C.

Charcot-Marie-Tooth disease type 4C (CMT4C) is an autosomal recessive demyelinating form of CMT characterized clinically by early onset and severe spinal deformities, and is caused by mutations in SH3TC2. We describe the case of a 10-year-old Japanese girl diagnosed with CMT4C. The patient developed progressive foot deformities such as marked pes cavus and ankle contracture, with mild muscle weakness in both legs, and generalized areflexia. On electrophysiological studies, motor nerve conduction velocity ranged from 22.3 m/s in the tibial nerve to 48.2 m/s in the median nerve. Sensory nerve conduction velocity ranged from 30.3 m/s in the sural nerve to 52.8 m/s in the median nerve. Sequence analysis of candidate genes identified two novel heterozygous mutations, c.229C>T and c.2775G>A, in SH3TC2. The patient was diagnosed as having CMT4C with novel mutations, making this the first documented Japanese pediatric case.

Cyclosporine for acute encephalopathy with biphasic seizures and late reduced diffusion.

BACKGROUND: Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is the most common syndrome among the acute encephalopathies, and is associated with a high incidence of neurologic sequelae. This study examined the efficacy of cyclosporine (CsA) for the treatment of AESD. METHODS: Fourteen children with AESD were recruited and categorized as group A (not receiving CsA) and group B (receiving CsA). Clinical course, laboratory data, magnetic resonance imaging (MRI), and outcome were analyzed retrospectively. We divided the patients into three types according to the distribution of abnormalities on MRI: frontal lobe predominant type, unilateral cerebral hemisphere type, and diffuse type. We used the Pediatric Cerebral Performance Category scale (PCPC) and the Pediatric Overall Performance Category scale (POPC) as prognostic measures. RESULTS: Of the 14 children, five were boys (age range, 9-32 months). PCPC score was: 1 for seven patients, 2 for three patients, and 3 for four patients. There was no significant difference in PCPC between groups A and B (P = 0.293). POPC score was: 1 for six patients, 2 for five patients, and 3 for three patients. There was a significant difference in POPC between groups A and B when patients with the frontal lobe predominant type were excluded (P = 0.020). CONCLUSIONS: CsA could improve the neurological prognosis of patients with AESD, except for those with frontal lobe predominant type.

Fulminant form of acute disseminated encephalomyelitis in a child treated with mild hypothermia.

We describe the case of a 3-year-old boy diagnosed with the fulminant form of acute disseminated encephalomyelitis (ADEM). He developed general fatigue, fever, drowsiness and difficulty in walking. He had extensive multiple high-intensity lesions in the white matter of the cerebrum and cerebellum, which are typical findings of ADEM. He became comatose and developed decerebrate rigidity with severe brain edema despite high-dose methylprednisolone therapy, and then was subjected to mild hypothermia therapy, and given i.v. immunoglobulin. The patient recovered remarkably with the sequela of only mild action tremor. The patient was considered to have acute hemorrhagic leukoencephalitis (AHLE), an extremely severe form of ADEM, in terms of the rapidly deteriorating clinical course and neuroimaging features. It was speculated that AHLE and ADEM might be a continuous disease spectrum. It is considered that the severe brain edema associated with ADEM or AHLE is a suitable indication for mild hypothermia therapy.

A novel NONO variant that causes developmental delay and cardiac phenotypes.

The Drosophila behavior/human splicing protein family is involved in numerous steps of gene regulation. In humans, this family consists of three proteins: SFPQ, PSPC1, and NONO. Hemizygous loss-of-function (LoF) variants in NONO cause a developmental delay with several complications (e.g., distinctive facial features, cardiac symptoms, and skeletal symptoms) in an X-linked recessive manner. Most of the reported variants have been LoF variants, and two missense variants have been reported as likely deleterious but with no functional validation. We report three individuals from two families harboring an identical missense variant that is located in the nuclear localization signal, NONO: NM_001145408.2:c.1375C > G p.(Pro459Ala). All of them were male and the variant was inherited from their asymptomatic mothers. Individual 1 was diagnosed with developmental delay and cardiac phenotypes (ventricular tachycardia and dilated cardiomyopathy), which overlapped with the features of reported individuals having NONO LoF variants. Individuals 2 and 3 were monozygotic twins. Unlike in Individual 1, developmental delay with autistic features was the only symptom found in them. A fly experiment and cell localization experiment showed that the NONO variant impaired its proper intranuclear localization, leading to mild LoF. Our findings suggest that deleterious NONO missense variants should be taken into consideration when whole-exome sequencing is performed on male individuals with developmental delay with or without cardiac symptoms.

White matter microstructural changes in tuberous sclerosis: Evaluation by neurite orientation dispersion and density imaging (NODDI) and diffusion tensor images.

Neurite orientation dispersion and density imaging (NODDI) is a novel diffusion method for evaluating tissue microstructure, and may provide additional information over conventional diffusion tensor imaging (DTI). We evaluated NODDI and DTI parameters in cases of tuberous sclerosis (TS) to assess microstructural changes in the white matter. Eleven cases of tuberous sclerosis and eight age-matched controls underwent NODDI and DTI. We performed qualitative analysis and tract-based spatial statistics (TBSS) analysis of the NODDI parameters (Ficv: intracellular volume fraction, Fiso: isotropic fraction, ODI: orientation dispersion index) as well as DTI parameters (MD: mean diffusivity, FA: fractional anisotropy). We also performed a correlation analysis between clinical symptoms and parameters. The qualitative analysis indicated that the Ficv had a lower value in TS cases particularly in the tubers adjacent to the white matter. The TBSS analysis showed that the TS cases had decreased Ficv in a greater area compared to the other parameters including MD. In particular, the Ficv was decreased in deep white matter, such as the superior longitudinal fascicles (SLF). The application of NODDI to TS cases revealed tissue microstructural changes, and particularly the Ficv could detect more widespread abnormalities in white matter structure compared to DTI parameters.

Epilepsy in Christianson syndrome: Two cases of Lennox-Gastaut syndrome and a review of literature.

Christianson syndrome (CS) is an X-linked intellectual disorder caused by mutations in the SLC9A6 gene. Clinical features of CS include an inability to speak, truncal ataxia, postnatal microcephaly, hyperkinesis, and epilepsy. Almost all patients with CS develop drug-resistant epilepsy-its most serious complication. We report two cases of CS with drug-resistant epilpesy associated with the Lennox-Gastaut syndrome (LGS). One patient experienced generalized tonic seizures since 9 months of age with cognitive regression, which evolved to include atonic seizures at the age of 7 years. Electroencephalography (EEG) showed generalized slow spike-wave complexes and generalized paroxysmal fast activity. Seizures remained drug-resistant despite multiple anti-seizure drugs. The second patient experienced generalized tonic seizures since the age of 17 months and arrested development. EEG showed generalized slow spike-wave complexes, with frequent atonic seizures since the age of 6 years. Electrical status epilepticus during slow-wave sleep (ESES) developed at the age of 7 years. Our cases illustrate that CS may cause LGS in addition to other developmental and epileptic encephalopathies of the neonatal and infantile period. We suggest that generalized tonic or tonic-clonic seizures and generalized slow spike-wave complexes in interictal EEG be included as potential electroclinical features of epilepsy in CS.

Serial Magnetic Resonance Imaging and 1H-Magnetic Resonance Spectroscopy in GABA Transaminase Deficiency: A Case Report.

Gamma-aminobutyric acid transaminase (GABA-T) deficiency is a rare, autosomal recessive disorder characterized by severe psychomotor retardation, early-onset epileptic encephalopathy, intractable seizures, hypotonia, and hyperreflexia. The disease is caused by mutation in the 4-aminobutyrate aminotransferase (ABAT) gene, which encodes an enzyme involved in GABA catabolism. In this chapter, a 10-year follow-up of GABA-T deficiency in a rare case of a long-term survivor patient is discussed. The patient showed a progression of clinical phases with increasing age. In infancy, the patient developed psychomotor retardation and recurrent encephalopathic episodes associated with febrile illness. In early childhood, the patient presented with refractory involuntary and hyperkinetic movements and dystonic hypertonicity. In childhood, the patient gradually progressed into the chronic stable phase of the condition. Magnetic resonance imaging demonstrated high signal intensity on diffusion-weighted images involving the internal and external capsules and cerebral white matter in infancy which disappeared gradually by the age of 3 years, and showed subsequently diffuse brain atrophy in childhood. Using proton magnetic resonance spectroscopy, GABA levels in the basal ganglia were shown to be markedly elevated at the age of 1-2 years, and subsequently decreased with increasing age (toward 5 years). These findings suggest that the encephalopathic episodes in infancy and clinical severity of involuntary and hyperkinetic movements may be correlated with levels of GABA in the basal ganglia. The high levels of GABA in the cerebrospinal fluid remained unaltered, whereas levels of GABA in the serum decreased during childhood. Further investigation of long-term clinical surveillance may improve the understanding of GABA-T deficiency.

[Preliminary trial of botulinum toxin A therapy for lower extremity spasticity in children with cerebral palsy].

Eleven children with gait disturbance due to cerebral palsy (mean age, 5.6 years, ranging from 2.4 to 11.5) were treated with Botulinum toxin A (BTA, BOTOX, Allergan) for improvement of spasticity and walking difficulty. BTA was injected into the gastrocnemius, adductors, and hamstring muscles with an initial total dose up to 8 units/kg or 100 units. Spasticity and gait disturbance were significantly improved in all patients 4 weeks after the treatment. Their parents also reported that BTA was helpful for brace tolerance and assistance of caregivers. No side effects including worsening of gait or signs of systemic adverse effects were observed. Management of leg spasticity with BTA is thought to be useful and safe, and approval for this use in Japan is recommended.

Phenotype of GABA-transaminase deficiency.

OBJECTIVE: We report a case series of 10 patients with γ-aminobutyric acid (GABA)-transaminase deficiency including a novel therapeutic trial and an expanded phenotype. METHODS: Case ascertainment, literature review, comprehensive evaluations, and long-term treatment with flumazenil. RESULTS: All patients presented with neonatal or early infantile-onset encephalopathy; other features were hypotonia, hypersomnolence, epilepsy, choreoathetosis, and accelerated linear growth. EEGs showed burst-suppression, modified hypsarrhythmia, multifocal spikes, and generalized spike-wave. Five of the 10 patients are currently alive with age at last follow-up between 18 months and 9.5 years. Treatment with continuous flumazenil was implemented in 2 patients. One patient, with a milder phenotype, began treatment at age 21 months and has continued for 20 months with improved alertness and less excessive adventitious movements. The second patient had a more severe phenotype and was 7 years of age at initiation of flumazenil, which was not continued. CONCLUSIONS: GABA-transaminase deficiency presents with neonatal or infantile-onset encephalopathy including hypersomnolence and choreoathetosis. A widened phenotypic spectrum is reported as opposed to lethality by 2 years of age. The GABA-A benzodiazepine receptor antagonist flumazenil may represent a therapeutic strategy.

Hereditary neuropathy with liability to pressure palsies in childhood: report of a case and a brief review.

We present a 10-year-old female diagnosed having hereditary neuropathy with liability to pressure palsies (HNPP). She had suffered from acute, recurrent monoplegic episodes affecting both the sciatic nerves and the left brachial plexus since the age of 7 years. The paresis seemed to be triggered by hiking and athletic training. Electrophysiological studies showed a conduction block in the proximal portions of affected nerves. The FISH method disclosed a deletion of the peripheral myelin protein 22 gene. This school child having HNPP is considered to be susceptible to the influence of abundant physical training, rather than minor trauma or compression at sites of entrapment of peripheral nerves.

Congenital disorder of glycosylation type Ic: report of a Japanese case.

Congenital disorders of glycosylation (CDG) are inherited metabolic diseases affecting N-linked glycosylation pathways with variable clinical presentations characterized by psychomotor retardation, seizures, ataxia and hypotonia. CDG-Ic is caused by mutation in the ALG6 gene encoding alpha-1,3-glucosyltransferase. We present a 9-year-old girl diagnosed as having CDG-Ic. She developed severe psychomotor retardation, epileptic seizures, muscle hypotonia, strabismus and some dysmorphic features without inverted nipples or fat pads. She showed a fluctuating serum transaminase level with or without some infection, and a characteristically low level of antithrombin III. MR imaging of the brain at age 2years demonstrated the lower limit of normal myelination, mild atrophy of the cerebrum, and mild hypoplasia of the brainstem and cerebellum. The patient exhibited a CDG type I pattern of serum transferrin on isoelectric focusing and mass spectrometric profiling. Sequence analysis of the ALG6 gene showed two heterozygous mutations, c.998C>T (A333V) and c.1061C>T (P354L). The patient was diagnosed as having CDG-Ic with a novel mutation, making her the first Japanese case. It was suggested that the severe psychomotor retardation in the patient was due to the existence of multiple mutant ALG6 alleles.

Acute encephalopathy of Bacillus cereus mimicking Reye syndrome.

We present an 11-year-old boy diagnosed as having acute encephalopathy and liver failure with the underlying condition of a metabolic dysfunction. He developed convulsions and severe consciousness disturbance following gastroenteritis after the ingestion of some fried rice. He showed excessive elevation of transaminases, non-ketotic hypoglycemia and hyperammonemia, which were presumed to reflect a metabolic dysfunction of the mitochondrial beta-oxidation, and he exhibited severe brain edema throughout the 5th hospital day. He was subjected to mild hypothermia therapy for encephalopathy, and treated with high-dose methylprednisolone, cyclosporine and continuous hemodiafiltration for liver failure, systemic organ damage and hyperammonemia. The patient recovered with the sequela of just mild intelligence impairment. In this case, Bacillus cereus, producing emetic toxin cereulide, was detected in a gastric fluid specimen, a stool specimen and the fried rice. It was suggested that the cereulide had toxicity to mitochondria and induced a dysfunction of the beta-oxidation process. The patient was considered as having an acute encephalopathy mimicking Reye syndrome due to food poisoning caused by cereulide produced by B. cereus.

Rasmussen syndrome combined with IgA deficiency and membranous nephropathy.

A 9-year-old boy diagnosed as having Rasmussen syndrome had congenital IgA deficiency and juvenile alopecia. He developed auditory hallucination and consciousness disturbance with intractable complex partial epileptic status. Anti-glutamate receptor epsilon2 antibodies were detected in his serum and cerebrospinal fluid. He was administered immunomodulatory agents and his seizures were treated with an intravenous anticonvulsant for 2 months. Subsequently, he developed a nephrotic syndrome, which proved to be membranous nephropathy and was treated with cyclophosphamide. Anti-basement membrane antibodies were detected in his serum. The boy died at the age of 14 years, and autopsy revealed diffuse brain atrophy with neuronal loss, infiltration of glial cells in the cerebrum, and loss of Purkinje cells in the cerebellum. A kidney specimen contained many sclerotic glomeruli, indicative of progressive membranous nephropathy. The patient was considered to have multimodal autoimmune disorder producing juvenile alopecia, autoimmune encephalitis, and a membranous nephropathy, based on the congenital IgA deficiency.

Salmonella encephalopathy successfully treated with high-dose methylpredonisolone therapy.

We present a 7-year-old boy diagnosed as having salmonella encephalopathy. He developed severe consciousness disturbance following enterocolitis. Electroencephalography showed diffuse and high-voltage slow activity but MR images of the brain were normal. Examination of inflammatory cytokines in serum and cerebrospinal fluid revealed high levels of interleukin-6, -8, and -10, and interferon gamma. Salmonella typhimurium was detected in a stool specimen. He was diagnosed as having salmonella-associated encephalopathy that had features of septic encephalopathy and quickly responded to high-dose methylpredonisolone therapy. High-dose methylpredonisolone was considered to be an effective treatment for hypercytokine-mediated S. encephalopathy.

A case of chronic recurrent cerebellar ataxia responding to steroid therapy.

We present a 25-month-old female having unusual cerebellar ataxia responsive to steroid therapy. She had suddenly suffered from action tremor and trunkal ataxia, following antecedent mild respiratory infection. These symptoms lasted for a month, and therefore she was referred to our hospital. No abnormal findings were disclosed for cerebrospinal fluid or MR images, but anti-glutamate receptor delta2 antibodies were detected in serum. MR spectroscopy of the cerebellum revealed a decrease in the N-acethylasparate/creatine ratio, suggesting micro-neuronal damage. She had quickly responded to high-dose methylpredonisolone therapy and the effectiveness of this steroid was reproducible in the subsequent relapses of ataxia. This clinical course seemed to be unique and was characterized as chronic recurrent cerebellar ataxia responding to steroid therapy.