PEX7 Mutations Cause Congenital Cataract Retinopathy and Late-Onset Ataxia and Cognitive Impairment: Report of Two Siblings and Review of the Literature

Adult Refsum disease (ARD) is a progressive multisystem disorder that is characterized by retinitis pigmentosa, hearing and smell loss, skeletal deformities, and elevated levels of phytanic acid (PA) in tissues. Peripheral neuropathy, cardiac abnormalities, and skin ichthyosis are considered subsequent manifestations, and are often described in patients not treated with PA dietary restriction. Mutations of the gene encoding the phytanoyl-coenzyme A (CoA) hydroxylase enzyme (PHYH) are the major genetic cause of ARD,1 and in a small number of cases a second gene, PEX7, which encodes peroxin 7 receptor protein (PEX7), has been associated with the ARD phenotype.2 We observed two Italian siblings who presented with late-onset progressive ataxia and cognitive decline. They comprised a 56-year-old woman and her 63-year-old brother, born from consanguineous parents, and presented with infantile bilateral cataract and retinitis pigmentosa. Except for the visual defect, both siblings exhibited normal psychomotor development. In adulthood (at age 40 years for the brother and 53 years for the sister), both patients manifested progressive behavioral and cognitive abnormalities associated with ataxic gait. At the latest examination, at ages 57 and 63 years, respectively, they presented with dementia (Mini-Mental State Examination scores of 19/30 and 13/30, respectively), motor apraxia, ophthalmoparesis, mild dysarthria, ataxic gait, mild limb dysmetria, Babinski sign, and decreased lower-limb deep-tendon reflexes. Neither of the patients had hearing loss, anosmia, or short metacarpals/metatarsals, and only the brother presented with dilated cardiomyopathy. Brain MRI revealed mild diffuse atrophy, and muscle biopsy sampling revealed normal morphology. Nerve conduction studies demonstrated a mild motor demyelinating neuropathy in the lower limbs, and somatosensory evoked potentials revealed a prolongation of the central conduction time. Both patients also presented with increased plasma PA levels (387.5 and 188.9 μmol/L), suggesting a diagnosis of ARD. Mutational screening of PHYH was negative, but there was a novel homozygous mutation in PEX7, p.Leu12Pro, caused by a T>C transition at nucleotide 35 (c.35T>C). This missense variation involved a well-conserved residue, and has not been reported as a single-nucleotide polymorphism (SNP) in the Human Gene Mutation Database, National Center for Biotechnology Information database for SNPs (dbSNP132ver) or Exome Variant Server. In silico analyses predicted the mutation as probably damaging: the scores were 0.98 (PolyPhen-2-HumDiv), 0.635 (PolyPhen-2-HumVar), and 0 (Sorting Tolerant From Intolerant). The parents were not available for segregation analysis, and an asymptomatic brother was found to be heterozygous for this mutation. The patients refused a skin biopsy procedure, preventing investigations of plasmalogen synthesis.3 PEX7 mutations are most frequently found in infants affected by rhizomelic chondrodysplasia punctata type 1 (RCDP1), a congenital and rapidly worsening syndrome that is charLorenzo Nanetti Viviana Pensato Valerio Leoni Manuela Rizzetto Claudio Caccia Franco Taroni Caterina Mariotti Cinzia Gellera