Affiliation:
1. IRCCS Ospedale Policlinico San Martino, UOC Medical Genetics Genoa Italy
2. Department of Neurosciences, Rehabilitation, Ophthalmology, Genetic and Maternal and Infantile Sciences University of Genoa Genoa Italy
3. IRCCS Istituto Giannina Gaslini, Medical Genetic Unit Genoa Italy
4. Department of Medical and Surgical Sciences Magna Graecia University of Catanzaro Catanzaro Italy
5. Regional Epilepsy Centre, “Bianchi‐Melacrino‐Morelli” Great Metropolitan Hospital Reggio Calabria Italy
6. IRCCS Ospedale Policlinico San Martino, UOC Neurology Clinic Genoa Italy
Abstract
AbstractAimBiallelic mutations in the PTRH2 gene have been associated with infantile multisystem neurological, endocrine, and pancreatic disease (IMNEPD), a rare autosomal recessive disorder of variable expressivity characterized by global developmental delay, intellectual disability or borderline IQ level, sensorineural hearing loss, ataxia, and pancreatic insufficiency. Various additional features may be included, such as peripheral neuropathy, facial dysmorphism, hypothyroidism, hepatic fibrosis, postnatal microcephaly, cerebellar atrophy, and epilepsy. Here, we report the first Italian family presenting only predominant neurological features.MethodsExtensive neurological and neurophysiological evaluations have been conducted on the two affected brothers and their healthy mother since 1996. The diagnosis of peripheral neuropathy of probable hereditary origin was confirmed through a sural nerve biopsy. Exome sequencing was performed after the analysis of major neuropathy‐associated genes yielded negative results.ResultsWhole‐exome sequencing analysis identified the homozygous substitution c.256C>T (p.Gln86Ter) in the PTRH2 gene in the two siblings. According to American College of Medical Genetics and Genomics (ACMG) guidelines, the variant has been classified as pathogenic.At 48 years old, the proband's reevaluation confirmed a demyelinating sensorimotor polyneuropathy with bilateral sensorineural hearing loss that had been noted since he was 13. Additionally, drug‐resistant epileptic seizures occurred when he was 32 years old. No hepatic or endocrinological signs developed. The younger affected brother, 47 years old, has an overlapping clinical presentation without epilepsy.InterpretationOur findings expand the clinical phenotype and further demonstrate the clinical heterogeneity related to PTRH2 variants. We thereby hope to better define IMNEPD and facilitate the identification and diagnosis of this novel disease entity.