Lichtenstein-Knorr Syndrome

A number sign (#) is used with this entry because of evidence that Lichtenstein-Knorr syndrome (LIKNS) is caused by homozygous mutation in the SLC9A1 gene (107310) on chromosome 1p36. One such family has been reported.

Description

Lichtenstein-Knorr syndrome is an autosomal recessive neurologic disorder characterized by postnatal onset of severe progressive sensorineural hearing loss and progressive cerebellar ataxia. Features usually develop in childhood or young adulthood (summary by Guissart et al., 2015).

Clinical Features

Heras Perez et al. (1986) reported a 5-generation family in which 8 individuals had severe progressive deafness and ataxia. Affected individuals had deafness beginning in infancy and were completely deaf by age 20 years; ataxia began in adolescence and resulted in loss of ability to walk at approximately age 30. The phenotype was consistent with Lichtenstein-Knorr syndrome.

Barbieri et al. (1986) reported a 43-year-old man who developed progressive and complete sensorineural hearing loss at age 25 and progressive cerebellar ataxia at age 30. Features of cerebellar ataxia included marked dysarthria, dizziness, and broad-based unsteady gait. Vibration sense was slightly impaired, and reflexes and muscle tone were slightly decreased. There was no family history of a similar disorder. Brain imaging showed cerebellar atrophy. Barbieri et al. (1986) concluded that the phenotype was most consistent with Lichtenstein-Knorr disease.

Striano et al. (1989) reported a 12-year-old girl, born of unrelated parents, who developed rapidly progressive sensorineural hearing loss at age 7 years. Around the same time, she developed progressive gait disturbances resulting in frank ataxia. Additional features included action tremor, dysmetria, dysdiadochokinesis, dysarthria, and nystagmus. Cognitive development was normal. Brain MRI showed thickening of the gray matter in the cortex and basal ganglia, reduction in the supra- and infratentorial white matter, and a hypoplastic corpus callosum.

Guissart et al. (2015) reported 3 sibs, born of consanguineous Turkish parents, with early-onset cerebellar ataxia and deafness. All patients had normal early development, but walking was delayed until ages ranging from 18 months to 5 years with aid. They later showed gait and limb ataxia with dysdiadochokinesis and dysmetria. Upper and lower limb areflexia suggested a peripheral neuropathy. Severe to profound sensorineural deafness was diagnosed between 12 and 20 months, and 2 patients showed lack of language and response on auditory-evoked stimulation. Brain imaging was normal in 1 patient, but showed very mild vermian atrophy in the other. One patient developed an episode of clonic jerks suggestive of seizures at age 14 years, but EEG was normal. The only male sib had delayed puberty and short stature at age 16.

Inheritance

The transmission pattern of LIKNS in the families reported by Heras Perez et al. (1986) and Guissart et al. (2015) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 3 sibs, born of consanguineous Turkish parents, with Lichtenstein-Knorr syndrome, Guissart et al. (2015) identified a homozygous missense mutation in the SLC9A1 gene (G305R; 107310.0001). The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Transfection of the mutation into Chinese hamster ovary cells showed that it caused reduced expression of the mutant protein (about 33% of control levels). The mutant protein was hypoglycosylated, did not localize properly to the cell surface, and had only about 2% residual activity compared to wildtype. Exome sequencing of the SLC9A1 gene in 172 additional patients with ataxia or deafness did not identify any further mutations.