Harel Yoon syndrome: a novel mutation in ATAD3A gene and expansion of the clinical spectrum.

BACKGROUND: Harel-Yoon syndrome (HAYOS) is a recently described neurodevelopmental disorder characterized by psychomotor delay, truncal hypotonia, appendicular spasticity, and peripheral neuropathy. It is caused by mutations in ATAD3A gene located on chromosome 1p.36.33 whose functions include mitochondrial DNA stabilization, the regulation of mitochondrial fission/fusion, and cholesterol homeostasis. MATERIALS AND METHODS: An 11-year-old male patient of consanguineous Egyptian parents, who present with neuroregression and ptosis along with progressive impaired vision, undergoes complete ophthalmological and neurological examination. Additionally, color fundus photography, fundus autofluorescence (FAF), spectral domain optical coherence tomography (SD-OCT) of both the macula and optic nerve head, full field electroretinogram (ERG), and visual field perimetry were obtained. Whole-exome sequencing and mitochondrial genome sequencing were done in a commercial laboratory from a peripheral blood sample. RESULTS: A novel mutation in ATAD3A gene c.624_644del was identified by whole-exome sequencing consistent with a diagnosis of Harel-Yoon Syndrome (HAYOS). The 11-year-old boy had characteristic features of neurodevelopmental delay, hypotonia, and peripheral neuropathy. However, we documented some novel features as fatiguable ptosis, facial weakness, progressive bulbar palsy, obsessive-compulsive disorder (OCD) in addition to cone system dysfunction. CONCLUSION: Our study reports a novel mutation in ATAD3A gene and expands the clinical spectrum of Harel-Yoon Syndrome. Future research aiming at better understanding of gene function will lead to better genotype-phenotype correlation and could pave the way to more treatment options.

A relatively common homozygous TRAPPC4 splicing variant is associated with an early-infantile neurodegenerative syndrome.

Trafficking protein particle (TRAPP) complexes, which include the TRAPPC4 protein, regulate membrane trafficking between lipid organelles in a process termed vesicular tethering. TRAPPC4 was recently implicated in a recessive neurodevelopmental condition in four unrelated families due to a shared c.454+3A>G splice variant. Here, we report 23 patients from 17 independent families with an early-infantile-onset neurodegenerative presentation, where we also identified the homozygous variant hg38:11:119020256 A>G (NM_016146.5:c.454+3A>G) in TRAPPC4 through exome or genome sequencing. No other clinically relevant TRAPPC4 variants were identified among any of over 10,000 patients with neurodevelopmental conditions. We found the carrier frequency of TRAPPC4 c.454+3A>G was 2.4-5.4 per 10,000 healthy individuals. Affected individuals with the homozygous TRAPPC4 c.454+3A>G variant showed profound psychomotor delay, developmental regression, early-onset epilepsy, microcephaly and progressive spastic tetraplegia. Based upon RNA sequencing, the variant resulted in partial exon 3 skipping and generation of an aberrant transcript owing to use of a downstream cryptic splice donor site, predicting a premature stop codon and nonsense mediated decay. These data confirm the pathogenicity of the TRAPPC4 c.454+3A>G variant, and refine the clinical presentation of TRAPPC4-related encephalopathy.

Childhood acute disseminated encephalomyelitis: an Egyptian pilot study.

Describing the variable clinical features, laboratory findings, neuroimaging findings, and treatments given to children who presented with ADEM and following them up both clinically and radiologically. 21 patients were recruited: 14 new cases, and 7 old ones presenting over the preceding 5 years (retrospective review of existing data). 11 males and 10 females, with a mean age of 4.4 years ± 2.7 SD, were included. All new patients were subject to full history, examination and a panel of investigations including MRI of the brain. Treatment was given in the form of pulsed methyl prednisolone or intravenous immunoglobulin (IVIG), followed by clinical and radiological follow-up every 3 months as needed. 11 cases occurred in spring, 8 post vaccine, of which 5 were after oral polio vaccine (OPV). MRI was done for all 21 patients and was abnormal in all of them, CT was done in only 10 patients as was normal in 9. Hyponatremia was seen in 11 patients. All patients who received corticosteroids showed prompt improvement. 6 out of 10 patients who received IVIG first failed treatment. Of the 17 treated patients, 10 had no sequelae and 10 had total lesion resolution on MRI at 3 months, versus 1 and 0 patients, respectively, in the untreated group. We found a disproportionately large number of post vaccination cases, especially after OPV. The association of ADEM with hyponatremia needs further study. MRI is central to diagnosis. Outcome is much better with treatment with steroids being far superior to IVIG. Excess use of IVIG should be discouraged.