Harel-Yoon Syndrome

A number sign (#) is used with this entry because of evidence that Harel-Yoon syndrome (HAYOS) is caused by heterozygous mutation in the ATAD3A gene (612316) on chromosome 1p36. One family with autosomal recessive inheritance has been reported.

Description

Harel-Yoon syndrome is a syndromic neurodevelopmental disorder characterized by delayed psychomotor development, intellectual disability, truncal hypotonia, spasticity, and peripheral neuropathy. Other more variable features such as optic atrophy may also occur. Laboratory studies in some patients show evidence of mitochondrial dysfunction (summary by Harel et al., 2016).

Clinical Features

Harel et al. (2016) reported 5 unrelated children ranging from 23 months to 9 years of age with a syndromic neurodevelopmental disorder. All had severely delayed psychomotor development with intellectual disability and poor or absent speech. The patients had truncal hypotonia, and all except the youngest showed appendicular spasticity and peripheral axonal neuropathy with atrophy of the lower limb muscles. Only the 9-year-old patient could walk, and she had a spastic crouched gait. Two patients had hypertrophic cardiomyopathy and 3 had optic atrophy. None had seizures. Additional variable features included poor feeding, sleep difficulties, myopia, nystagmus, and esotropia. Some patients had skeletal anomalies, such as pectus carinatum, scoliosis, hip dysplasia, or foot deformities. Some patients had dysmorphic features, including high forehead, small nose, deep-set eyes, and micrognathia, but there was not a common pattern. Three patients had evidence of mitochondrial dysfunction, including increased serum lactate, deficiencies of mitochondrial respiratory enzymes, and methylglutaconic aciduria.

Clinical Variability

Harel et al. (2016) reported 2 adult sibs, born of distantly related Italian parents, with HAYOS. The transmission pattern in this family was consistent with autosomal recessive inheritance. The patients had delayed development since infancy, language delay, hypotonia, congenital cataracts, and ataxic gait. One had mild intellectual disability. Dysmorphic facial features included long face, triangular nose, and prognathia with a prominent chin. Both patients developed absence seizures around 6 to 7 years of age. Other features included mildly delayed puberty and delayed bone age. Brain imaging showed progressive cerebellar atrophy and hypoplastic optic nerves. Mitochondrial respiratory chain enzyme analysis in muscle and fibroblasts showed normal activities. Whole-exome sequencing identified a homozygous missense variant in the ATAD3A gene (T53I; 612316.0002); functional studies of the variant were not performed. Each unaffected parent was heterozygous for the mutation.

Molecular Genetics

In 5 unrelated children with HAYOS, Harel et al. (2016) identified a recurrent de novo missense mutation in the ATAD3A gene (R528W; 612316.0001). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies of the R528W variant were not performed. Fibroblasts from 1 patient showed decreased mitochondria and mitophagic vesicles. Generation of the homologous mutation (R534W) in the Drosophila 'bor' gene resulted in lethality when expressed ubiquitously, in all neurons, or in motor neurons. Muscle-specific expression of the mutation in Drosophila led to 90% lethality and was associated with decreased mitochondrial content, aberrant mitochondrial morphology, and increased autophagic vacuoles. These findings suggested that the mutation acts as a toxic gain-of-function allele and results in decreased mitochondria in neurons and muscle.