Genetic and clinical landscape of childhood cerebellar hypoplasia and atrophy.

PURPOSE: Cerebellar hypoplasia and atrophy (CBHA) in children is an extremely heterogeneous group of disorders, but few comprehensive genetic studies have been reported. Comprehensive genetic analysis of CBHA patients may help differentiating atrophy and hypoplasia and potentially improve their prognostic aspects. METHODS: Patients with CBHA in 176 families were genetically examined using exome sequencing. Patients with disease-causing variants were clinically evaluated. RESULTS: Disease-causing variants were identified in 96 of the 176 families (54.5%). After excluding 6 families, 48 patients from 42 families were categorized as having syndromic associations with CBHA, whereas the remaining 51 patients from 48 families had isolated CBHA. In 51 patients, 26 aberrant genes were identified, of which, 20 (76.9%) caused disease in 1 family each. The most prevalent genes were CACNA1A, ITPR1, and KIF1A. Of the 26 aberrant genes, 21 and 1 were functionally annotated to atrophy and hypoplasia, respectively. CBHA+S was more clinically severe than CBHA-S. Notably, ARG1 and FOLR1 variants were identified in 2 families, leading to medical treatments. CONCLUSION: A wide genetic and clinical diversity of CBHA was revealed through exome sequencing in this cohort, which highlights the importance of comprehensive genetic analyses. Furthermore, molecular-based treatment was available for 2 families.

Anti-epileptics alter hypothyroidism of patients with severe motor and intellectual disabilities.

Objective: Anti-epileptic drugs, such as carbamazepine (CBZ) or phenytoin, may induce hypothyroidism in epilepsy patients. We assessed thyroid function of chronic patients with severe motor and intellectual disabilities (SMID) in our hospital. Methods: We examined thyroid-stimulating hormone (TSH), free thyroxine (fT4), and free thyronine (fT3) in 73 patients with SMID (47 men and 26 women, average age 48.4 years, range 30-68 years) without thyroid hormone supplement therapy. We determined the relationship between the thyroid function of patients taking the anti-epileptic drugs CBZ, valproate (VPA), and phenobarbital, other medications including anti-psychotic drugs, and treatments without anti-epileptic or anti-psychotic drugs. Results: TSH levels were not significantly different between the groups taking CBZ (CBZ+med), other anti-epileptic drugs or anti-psychotic drugs (CBZ-med), and only medications without anti-epileptic or anti-psychotic drugs (Non-med). The CBZ+med group had significantly lower fT4 levels than the CBZ-med or Non-med groups. There was a negative correlation between thyroid function level and the phenobarbital groups. TSH levels of the VPA+med group were significantly higher than VPA-med and Non-med group; fT3 and fT4 levels were not significantly different. Conclusions: Our results indicate that hypothyroidism may be present in patients with SMID taking anti-epileptic drugs. This suggests it is important to regularly measure thyroid function in patients with SMID taking anti-epileptic drugs, especially CBZ.

The first genetically confirmed Japanese patient with mucolipidosis type IV.

Mucolipidosis type IV (MLIV) is a rare neurodegenerative disorder characterized by severe psychomotor delay and visual impairment. We report the brain pathology in the first Japanese patient of MLIV with a novel homozygous missense mutation in MCOLN1. We detected the localized increase in p62-reactive astrocytes in the basal ganglia.

Ulcers on the epiglottis caused by a nasogastric tube in three adults with severe motor and intellectual disabilities.

Nasogastric tube feeding is a common method of parenteral nutrition. We observed ulcers on the epiglottis caused by a nasogastric tube in three adults with severe motor and intellectual disabilities (SMID) during examination with a laryngeal fiberscope while swallowing. These ulcers were healed by changing the method of inserting the nasogastric tube. The patients were three men aged 25, 39, and 55 years. The muscle tone of the whole body was increased in all of the patients. Two patients had severe scoliosis, and the other patient had lordosis in the thoracic vertebrae and had received laryngo-tracheal diversion. All of the patients received intermittent or continuous respiratory care. The pharynx of the patients with severe scoliosis became thinner and the feeding tubes ran obliquely. The feeding tube in the patient who received laryngo-tracheal diversion entered the cut and closed trachea through the glottis. Ulcers were observed on the laryngeal side of the epiglottis in all of the patients. The ulcers were healed by preventing feeding tubes from running obliquely or by using the naso-gastric tube made of different materials in the patients with severe scoliosis. In the patient who received laryngo-tracheal diversion, we succeeded in avoiding the glottis by keeping his face forward while inserting the feeding tube. Then feeding tubes were changed with guidewires, and the ulcers were healed. When using nasogastric tube feeding for persons with SMID with a large increase in muscle tone and/or with severe scoliosis, adopting a method of inserting feeding tubes that avoids damaging the epiglottis with a laryngeal fiberscope is required.

A case of megalencephalic leukoencephalopathy with subcortical cysts (van der Knaap disease): molecular genetic study.

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is an autosomal recessive disorder characterized by macrocephaly, deterioration of motor function with ataxia, spasticity and mental decline. It has been revealed that the mutations in the gene, KIAA0027, were responsible for MLC and the gene was renamed subsequently 'MLC1'. A 41-year-old Japanese male with MLC, in whom a homozygous missense mutation, TCG to TTG at codon 93 resulting in S93L, was detected in the MLC1 gene, was described. MRI revealed marked cerebral atrophy and enlargement of the ventricular system. The subject's motor function had severely deteriorated, while his cognitive function had maintained at the level of a 2-year-old for the past 10 years. The mutation in the MLC1 gene of the patient is considered to be a common mutation responsible for MLC in Japanese patients because the same mutation had been detected in two other Japanese patients with MLC.