Intrafamilial phenotypic heterogeneity in a Taiwanese family with a MAPT p.R5H mutation: a case report and literature review

Abstract

Background: Frontotemporal degeneration (FTD) is a clinically and genetically heterogeneous neurodegenerative disorder characterized by deficits in executive function that frequently overlaps with parkinsonism and motor neuron disorders. Several genes have been identified to cause autosomal dominant forms of FTD, including the gene coding for the protein associated with microtubule tau (MAPT). While most reported pathogenic mutations in MAPT occur in exons 9-13, few families have been reported with mutations outside of this region. Herein, we report a first Taiwanese family having the exon 1 p.Arg5His mutation in MAPT with intrafamilial phenotype heterogeneity.

Case presentation: A 63-year-old man presented with progressive non-fluent speech and impaired memory for 3 years. He then developed apraxia, myoclonus and parkinsonism feature at his right hand. Extensive neurologic and neurocognitive examination lead to a diagnosis of FTD mixed with corticobasal syndrome. Magnetic resonance imaging revealed asymmetric atrophy in the left frontal and temporal lobes and single-photon emission computed tomography indicated decreased metabolism in the same areas as well as the left basal ganglia. The patient's mother had been diagnosed with amyotrophic lateral sclerosis (ALS) at the age of 60 and was deceased 10 years later due to respiratory failure. The patient's younger sister had persistent depressive disorder in her early forties and did not have any prominent cognitive or motor dysfunctions. We performed genetic analysis applying a targeted next generation sequencing (NGS) panel covering MAPT, GRN, VCP, FUS, CHMP2B, and TARDBP on the proband, followed by Sanger sequencing of candidate genes in eight family members. Hexanucleotide repeat expansion of C9Orf72 was determined by repeat-primed PCR. We identified a missense mutation in exon 1 of MAPT gene, c.14G > A (p.R5H), which was previously reported in only two Japanese patients in a literature review. This substitution co-segregated with the disease phenotypes in the family.

Conclusions: This is the first report of the occurrence of the MAPT p.R5H mutation in the Taiwanese population. Our findings extend the current knowledge of phenotypic heterogeneity among family members carrying the MAPT p.R5H mutation.

Keywords: Amyotrophic lateral sclerosis; Corticobasal syndrome; Depression; Frontotemporal dementia; Microtubule-associated protein tau; Primary progressive aphasia.

Fig. 1

Brain MRI of the index patient. a-e T1WI MRI series showed focal atrophy in the posterior frontal premotor cortex (a-c, arrows) and superior temporal gyrus (d, e, arrows). f SPECT revealed decreased metabolism in left temporal and occipital cortex (arrows)

Fig. 2

Family pedigree and genetic analysis of the index patient. Index family pedigree. Black symbols denote family members affected with FTD, ALS, or PDD. The proband described in the current study is marked with an arrow. mt, mutated alleles; wt, normal alleles

Fig. 3

Chromatograms of direct sequencing of the MAPT genomic sequence. Genetic analysis revealed a single nucleotide change (c.14G > A, p.R5H, right panel) compared to the wild type sequence (left panel). The mutations identified in this study were located in the indicated position