Cerebellar Ataxia and Peripheral Neuropathy in a Family With PNPLA8 -Associated Disease

Abstract

ObjectivesTo describe clinical and genetic findings in 2 siblings with slowly progressive ataxia.MethodsWe studied 2 adult siblings through detailed physical and instrumental examinations. Whole-exome sequencing was used to identify an underlying genetic cause.ResultsBoth siblings presented with adolescence-onset ataxia, progressive sensorimotor polyneuropathy, and preserved cognition over time. The onset of symptoms was between 10 and 14 years of age. A brain MRI demonstrated mild cerebellar atrophy in the older brother at age 45 years. Exome sequencing revealed compound heterozygous loss-of-function variants c.2269del (p.(Thr757GlnfsTer10)) and c.2275_2276del (p.(Leu759AlafsTer4)) inPNPLA8. The novel variant c.2269del results in frameshift with a premature stop codon p.(Thr757GlnfsTer10) and loss of normal enzyme function.DiscussionOur findings support the theory that biallelic loss-of-functionPNPLA8variants are involved in neurodegenerative mitochondrial disease. Compared with patients previously described, these patients' phenotype may be interpreted as a milder phenotype associated with a slight progression of ataxia throughout adulthood.

Delineating the phenotype of PNPLA8‐related mitochondriopathies

“…In an attempt to delineate the clinical spectrum underling PNPLA8 and possible phenotype and genotype correlations, detailed clinical and neuroimaging assessment were performed for three Egyptian patients and compared with the literature (Table 1). 3–6 Similar to the two previously reported cases with congenital onset 4,5 (Table 1), Patient 1 in our study presented with congenital microcephaly, myoclonic seizures and predominantly refractory epilepsy. Prenatal ultrasound in previous reports documented congenital microcephaly and cerebellar atrophy in the second 5 and third trimester 4 .…”

“…Moreover, progressive brain atrophy was also noted. Recently, adulthood onset ataxia with peripheral neuropathy was also observed with pathogenic variants of PNPLA8 6 . Interestingly, patients with either childhood or adulthood onset usually harbor compound heterozygous truncating PNPLA8 variants.…”

“…They were five protein truncating (three frameshift and two nonsense) and one missense variant. Interestingly, the c.2275_2276del (p.Leu759AlafsTer4) was identified in the heterozygous form in three unrelated families 3,4,6 …”

“…They showed different clinical phenotypes: two patients presented with congenital microcephaly, early onset epilepsy and spasticity 4,5 while childhood onset epilepsy followed by neurodegeneration was reported in another two patients 3,4 . Finally, adulthood ataxia with peripheral axonal neuropathy and normal cognitive abilities were documented in two sibs 6 . All reported patients demonstrated significant phenotypic heterogeneity, typically lethal in the neonatal form and less severe in the childhood onset.…”

“…The current knowledge about the clinical phenotype caused by biallelic pathogenic variants in the PNPLA8 is limited to six cases 3–6 . They showed different clinical phenotypes: two patients presented with congenital microcephaly, early onset epilepsy and spasticity 4,5 while childhood onset epilepsy followed by neurodegeneration was reported in another two patients 3,4 .…”