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We report the first clinical-radiological-genetic-molecular-pathological study of a kindred with c.823-10G>T MAPT intronic variant (rs63749974) associated with frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). We describe the clinical spectrum within this family and emphasize the association between MAPT gene variants and motor neuron disease. This report of a second family with FTDP-17 associated with c.823-10G>T MAPT variant strongly supports pathogenicity of the variant and confirms it is a 4-repeat (4R) tauopathy. This intronic point mutation, probably strengthens the polypyrimidine tract and alters the splicing of exon 10 (10 nucleotides into intron 9) close to the 3' splice site.

Mutations in the Presenilin 1 (PSEN1) gene are the most common cause of autosomal dominant familial Alzheimer's disease. We report the clinical, imaging and postmortem findings of kindred carrying a novel duplication mutation (Ile168dup) in the PSEN1 gene. We interpret the pathogenicity of this novel variant and discuss the additional neurological features (pyramidal dysfunction, myoclonus and seizures) that accompanied cognitive decline. This report broadens the clinical phenotype of PSEN1 insertion mutations while also highlighting the importance of considering duplication, insertion and deletion mutations in cases of young onset dementia.

We report a patient with Charcot-Marie-Tooth disease (CMT) due to the p.Ile112Thr mutation in myelin protein zero (MPZ) who presented with a patchy neuropathy with conduction block and tonic pupils. Conduction block is unusual in inherited neuropathies, while pupil abnormalities are recognised to occur in CMT especially due to MPZ mutations. This case highlights that patchy demyelinating neuropathy with conduction block may occur in p.Ile112Thr MPZ mutations. Involvement of the pupils, as in this case, may be a pointer towards a genetic rather than inflammatory cause of neuropathy.

Charcot-Marie-Tooth disease (CMT) is the commonest hereditary neuropathy encompassing a large group of clinically and genetically heterogeneous disorders. The commonest form of CMT, CMT1A, is usually caused by a 1.4 megabase duplication of chromosome 17 containing the PMP22 gene. Mutations of PMP22 are a less common cause of CMT. We describe clinical, electrophysiological and molecular findings of 10 patients carrying PMP22 missense mutations. The phenotype varied from mild hereditary neuropathy with liability to pressure palsies (HNPP) to severe CMT1. We identified six different point mutations, including two novel mutations. Three families were also found to harbour a Thr118Met mutation. Although PMP22 point mutations are not common, our findings highlight the importance of sequencing the PMP22 gene in patients with variable CMT phenotypes and also confirm that the PMP22 Thr118Met mutation is associated with a neuropathy albeit with reduced penetrance.

A GGGGCC repeat expansion in the C9orf72 gene was recently identified as a major cause of familial and sporadic amyotrophic lateral sclerosis and frontotemporal dementia. There is suggestion that these expansions may be a rare cause of parkinsonian disorders such as progressive supranuclear palsy (PSP), multiple system atrophy (MSA), and corticobasal degeneration (CBD). Screening the C9orf72 gene in 37 patients with features of corticobasal syndrome (CBS) detected an expansion in 3 patients, confirmed by Southern blotting. In a series of 22 patients with clinically diagnosed PSP, we found 1 patient with an intermediate repeat length. We also screened for the C9orf72 expansion in a large series of neuropathologically confirmed samples with MSA (n = 96), PSP (n = 177), and CBD (n = 18). Patients were found with no more than 22 GGGGCC repeats. Although these results still need to be confirmed in a larger cohort of CBS and/or CBD patients, these data suggest that in the presence of a family history and/or motor neuron disease features, patients with CBS or clinical PSP should be screened for the C9orf72 repeat expansion. In addition, we confirm that the C9orf72 expansions are not associated with pathologically confirmed MSA, PSP, or CBD in a large series of cases.

Recurrent rhabdomyolysis complicates a number of inherited muscle and metabolic disorders and represents a serious, potentially life-threatening condition which frequently requires critical care. Identification of the underlying genetic cause has traditionally relied upon detailed history and examination findings which subsequently guide the investigative work-up. However, in many cases the causative molecular defect remains undetermined. This study aims to investigate whether utilising next-generation sequencing (NGS) technology early in the diagnostic pathway might offer a rapid, cost-effective tool for the diagnosis of patients with recurrent attacks of rhabdomyolysis when a genetic aetiology is suspected. We have designed a “rhabdomyolysis gene panel” comprised of 48 genes known or predicted to cause rhabdomyolysis using NGS technology. Over 200 patients have been recruited. In addition, array CGH and whole exome sequencing may be used. A pilot study of 53 patients with a panel of sequenced 35 rhabdomyolysis genes using an amplicon based sequencing panel on an Illumina MiSeq was performed. 52 of the first 53 first evaluated patients have a variant in at least 1 gene. 49 patients have heterozygous variants in at least two different genes. We identified 15 cases out of 52 with probable pathogenic mutations using this approach. The pilot study showed that the rhabdomyolysis genetic panel is a potentially useful way to identify genetic alterations in patients with rhabdomyolysis. The high number of symptomatic patients with mutations identified in more than one gene associated with rhabdomyolysis suggests that gene–gene interaction(s) may play an important role. We are currently preparing a new extended panel of 48 genes.

CMTX1 is the second most common cause of Charcot-Marie-Tooth disease (CMT), usually caused by mutations in the Cx32 gene. Cx32 has two tissue-specific promoters: P1, specific for liver and pancreas, and P2 which is nerve specific. Over 300 mutations have been described in Cx32 , spread throughout the coding region. However, 10% of CMTX1 families do not have mutations in the coding region. To date, 5 noncoding region mutations have been reported. We describe two families with X-linked inheritance and a phenotype consistent with CMTX1 who did not have mutations in the Cx32 coding region. Family 1 were negative for mutations in PMP22, MPZ, SPTLC1 and GDAP1 Family 2 were negative for mutations in MPZ and rearrangements at chromosome 17p11.2. The noncoding region of Cx32 was sequenced and an upstream exon-splicing variant found at c.-373G>A which segregated with the disease in both families. This variant is located at the last base of the nerve-specific 5′UTR exon and thus may disrupt splicing of the nerve-specific transcript. Online consensus splice-site programs predict a reduced score for the mutant sequence vs the normal sequence. Two other mutations have previously been described within the 5′UTR region, which created a potential donor splice site and were shown to prevent translation of mutant mRNA. It is likely that other mutations within the Cx32 noncoding regions account for the CMTX1 families who do not have coding region mutations.

Distal muscle weakness and atrophy is the presenting symptom of both distal myopathies and distal motor neuropathies. Differential diagnosis might be complicated by the coexistence of secondary axonal changes in primary distal myopathies, or the identification of unspecific myopathic changes on muscle biopsies in neuropathies. We report a two generations Caucasian family with at least 3 affected family members presenting with distal weakness and pes cavus in the teens. The index case was referred to us at the age of 14 years, due to Achilles tendon contractures and equinovarus feet deformity; he could not heel walk, had lower leg muscles wasting and, to a lesser extent, of the thenar and hypothenar eminence. His muscle power was within normal limits except for subgravity ankles plantar and dorsiflexion; deep tendon reflexes were preserved. The electrophysiology was suggestive of a motor neuronopathy. His younger sister presented in her teens with similar problems associated with mild hands weakness. Her electrophysiology was suggestive of a motor neuronopathy while the muscle MRI of the legs was suggestive of a distal myopathy. Their father presented in his forties with increased walking difficulties and frequent falls. The whole exome analysis in these affected individuals unrevealed two independent mutations: a heterozygous Myosin Heavy Chain 7 gene mutation (MYH7, g.23884965C > T,c.5030G > A, p.R1677H) and a heterozygous mutation in the Berardinelli-Seip Congenital Lypodystrophy type 2 gene (BSCL2, g.62469971T > G, p.N88S), present in each of the affected individuals. Our report highlights the power of whole exome sequencing in identifying the mutation load responsible for the phenotype in this family and suggests that “double trouble” of conditions with overlapping clinical features may be easily missed by more traditional diagnostic approaches.

An intronic expansion of a hexanucleotide GGGGCC repeat in the C9ORF72 gene has recently been shown to be an important cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in familial and sporadic cases. The frequency has only been defined in a small number of populations where the highest sporadic rate was identified in Finland (21.1%) and the lowest in mainland Italy (4.1%). We examined the C9ORF72 expansion in a series of 146 Greek ALS cases, 10.95% (n = 16) of cases carried the pathological expansion defined as greater than 30 repeats. In the 10 familial ALS probands, 50% (n = 5) of them carried a pathologically large expansion. In the remaining 136 sporadic ALS cases, 11 were carriers (8.2%). None of the 228 Greek controls carried an expanded repeat. The phenotype of our cases was spinal (13/16) or bulbar (3/16) ALS, the familial cases were all spinal ALS and none of our cases had behavioral frontotemporal dementia. Expansions in the C9ORF72 gene therefore represent a common cause of ALS in Greece and this test will be diagnostically very important to implement in the Greek population. The frequency is higher than other populations with the exception of Finland and this may be due to Greece being a relatively isolated population.