eNeurologicalSci · 2018
Gordon Holmes syndrome due to compound heterozygosity of two new PNPLA6 variants - A diagnostic challenge.
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Salgado Paula, Carvalho Rui, Brandão Ana Filipa, Jorge Paula, Ramos Cristina, Dias Daniel, Alonso Isabel, Magalhães Marina
Аннотация
BACKGROUND: Gordon Holmes syndrome (GHS), characterized by cerebellar ataxia and hypogonadotropic hypogonadism (HH), has been related to recessive mutations in PNPLA6 gene.
AIMS OF THE STUDY: Describe one Portuguese family with GHS due to compound heterozygosity of two new PNPLA6 variants.
METHODS: Report on the clinical presentation, diagnostic and genetic workup to reach GHS diagnosis.
RESULTS: The index case presented with slight cognitive impairment and primary amenorrhea, developed at the age of 25 a cerebellar syndrome. Her neurological exam revealed ataxia and mild extrapyramidal syndrome. She was born from non-consanguineous parents and had 8 siblings. Two of her sisters also had history of primary amenorrhea, tremor and ataxia. All 3 were diagnosed with HH and previous FMR1 gene screening on her sisters revealed a 51 CGGs allele. However, 2 normal-sized FMR1 alleles were identified on the proband thus excluding the FXTAS diagnosis in the family. Further PNPLA6 variant screening revealed 2 novel variants in compound heterozygosity [c.2404G > C]; [c.4081C > T], which co-segregated with the disease.
CONCLUSIONS: This case shows how incomplete studies can be misleading, increases genetic knowledge of GHS and expands its clinical spectrum. The coexistence of a FMR1 intermediate allele in this family constituted an additional challenge in the etiological investigation.
AIMS OF THE STUDY: Describe one Portuguese family with GHS due to compound heterozygosity of two new PNPLA6 variants.
METHODS: Report on the clinical presentation, diagnostic and genetic workup to reach GHS diagnosis.
RESULTS: The index case presented with slight cognitive impairment and primary amenorrhea, developed at the age of 25 a cerebellar syndrome. Her neurological exam revealed ataxia and mild extrapyramidal syndrome. She was born from non-consanguineous parents and had 8 siblings. Two of her sisters also had history of primary amenorrhea, tremor and ataxia. All 3 were diagnosed with HH and previous FMR1 gene screening on her sisters revealed a 51 CGGs allele. However, 2 normal-sized FMR1 alleles were identified on the proband thus excluding the FXTAS diagnosis in the family. Further PNPLA6 variant screening revealed 2 novel variants in compound heterozygosity [c.2404G > C]; [c.4081C > T], which co-segregated with the disease.
CONCLUSIONS: This case shows how incomplete studies can be misleading, increases genetic knowledge of GHS and expands its clinical spectrum. The coexistence of a FMR1 intermediate allele in this family constituted an additional challenge in the etiological investigation.