Pierre R. Bourque

Evidence for an oligogenic basis of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with a substantial heritable component. In pedigrees affected by its familial form, incomplete penetrance is often observed. We hypothesized that this could be caused by a complex inheritance of risk variants in multiple genes. Therefore, we screened 111 familial ALS (FALS) patients from 97 families, and large cohorts of sporadic ALS (SALS) patients and control subjects for mutations in TAR DNA-binding protein (TARDBP), fused in sarcoma/translated in liposarcoma (FUS/TLS), superoxide dismutase-1 (SOD1), angiogenin (ANG) and chromosome 9 open reading frame 72 (C9orf72). Mutations were identified in 48% of FALS families, 8% of SALS patients and 0.5% of control subjects. In five of the FALS families, we identified multiple mutations in ALS-associated genes. We detected FUS/TLS and TARDBP mutations in combination with ANG mutations, and C9orf72 repeat expansions with TARDBP, SOD1 and FUS/TLS mutations. Statistical analysis demonstrated that the presence of multiple mutations in FALS is in excess of what is to be expected by chance (P = 1.57 × 10(-7)). The most compelling evidence for an oligogenic basis was found in individuals with a p.N352S mutation in TARDBP, detected in five FALS families and three apparently SALS patients. Genealogical and haplotype analyses revealed that these individuals shared a common ancestor. We obtained DNA of 14 patients with this TARDBP mutation, 50% of whom had an additional mutation (ANG, C9orf72 or homozygous TARDBP). Hereby, we provide evidence for an oligogenic aetiology of ALS. This may have important implications for the interpretation of whole exome/genome experiments designed to identify new ALS-associated genes and for genetic counselling, especially of unaffected family members.

A CASE OF ALS-FTD IN A LARGE FALS PEDIGREE WITH A K17I ANG MUTATION

Approximately 90% of amyotrophic lateral sclerosis (ALS) cases are sporadic (SALS), but 10% are familial (FALS). Mutations in SOD1, Alsin , Dynactin , SETX , DJ-1 , VAPB , and TDP-431 have been reported (table e-1 on the Neurology ® Web site at www.neurology.org). After the identification of sequence variation VEGF in patients with ALS, mutations in another angiogenic gene ( ANG ) were identified in SALS and FALS.2,3 Studies in other populations have identified ANG mutations in patients with ALS, but also in healthy controls. This suggests that not all mutations are pathogenic.3,4 ### Methods. A total of 39 unrelated FALS patients, negative for SOD1 mutations, were screened for ANG mutations. This study was approved by the local ethics committee and participants provided informed consent. DNA was isolated from venous blood and ANG mutation analysis was performed as described in appendix e-1. A total of 275 unrelated, healthy controls were taken from a prospective population-based study on ALS in The Netherlands and were also screened.5 PMut (http://mmb2.pcb.ub.es:8080/PMut/) was used to predict the impact of an amino acid substitution on the structure and function of the protein. ### Results. We identified one mutation in one patient (122 A>T) (figure, A), leading to an amino acid substitution of lysine to isoleucine (K17I) (figure, B). PMut analysis predicted this mutation to be pathogenic. Sequence alignments of ANG in different species …

Musical auditory hallucinosis from listeria rhombencephalitis

BACKGROUND Complex auditory hallucinations have rarely been reported in cases of brainstem stroke or tumor. METHOD Case study. RESULTS A patient with acute Listeria rhombencephalitis complained of formed musical auditory hallucinations on the side of recent sensorineural deafness. MRI revealed an abscess in the middle cerebellar peduncule with extensive surrounding edema. CONCLUSIONS Disruption of brainstem auditory pathways may cause complex auditory hallucinations. Potential pathogenetic mechanisms are discussed and a diagnostic approach is proposed.

Vasculitic basilar artery thrombosis in chronic Candida albicans meningitis

BACKGROUND Cerebrovascular complications of meningitis have been most extensively documented in the setting of acute bacterial or chronic tuberculous meningitis. Involvement of major cerebral vessels is rare and basilar artery thrombosis has not been reported in fungal meningitis secondary to candida infection. METHODS We describe the clinical course and neuropathological findings in a woman with chronic meningitis due to Candida albicans. RESULTS The diagnosis remained elusive antemortem despite analysis of 7 large volume CSF samples and examination of a meningeal and cortical biopsy. Death followed extensive brainstem and temporo-occipital infarction secondary to basilar artery thrombosis. The basilar artery occlusion was secondary to an intense, granulomatous and necrotizing basal meningitis focally extending to the media and intima. CONCLUSIONS This paroxysmal and devastating complication of untreated chronic candida meningitis reinforces that a trial of empirical therapy with both antituberculous and antifungal agents should be considered in most cases of chronic culture-negative lymphocytic meningitis.

Myopathy with hexagonally cross-linked tubular arrays: a new autosomal dominant or sporadic congenital myopathy.

We describe a slowly progressive myopathy with unique crystalloid inclusions in type 2 muscle fibers in a father and his son, as well as one more unrelated individual. The inclusions were strongly eosinophilic and purple by the Gomori method. They were composed of vesicular profiles, approximately 20 nm in cross‐diameter, connected by radially arranged double spokes arising at 60° angles. The inclusions were not related to any normal cellular organelle. Extensive immunohistochemical studies failed to reveal their chemical nature. It is suggested that this is a new congenital myopathy with characteristic intracytoplasmic inclusions, occurring sporadically or with an autosomal dominant pattern of inheritance. Ann Neurol 1999;45:512–515

Whole-exome sequencing is a valuable diagnostic tool for inherited peripheral neuropathies: outcomes from a cohort of 50 families

The inherited peripheral neuropathies (IPNs) are characterized by marked clinical and genetic heterogeneity and include relatively frequent presentations such as Charcot‐Marie‐Tooth disease and hereditary motor neuropathy, as well as more rare conditions where peripheral neuropathy is associated with additional features. There are over 250 genes known to cause IPN‐related disorders but it is estimated that in approximately 50% of affected individuals a molecular diagnosis is not achieved. In this study, we examine the diagnostic utility of whole‐exome sequencing (WES) in a cohort of 50 families with 1 or more affected individuals with a molecularly undiagnosed IPN with or without additional features. Pathogenic or likely pathogenic variants in genes known to cause IPN were identified in 24% (12/50) of the families. A further 22% (11/50) of families carried sequence variants in IPN genes in which the significance remains unclear. An additional 12% (6/50) of families had variants in novel IPN candidate genes, 3 of which have been published thus far as novel discoveries (KIF1A, TBCK, and MCM3AP). This study highlights the use of WES in the molecular diagnostic approach of highly heterogeneous disorders, such as IPNs, places it in context of other published neuropathy cohorts, while further highlighting associated benefits for discovery.

Spontaneous thoracic spinal cord herniation

A 69-year-old woman presented with insidiously progressive and disabling pain in the right leg. There was no history of trauma or surgery. An examination revealed features suggestive of thoracic level Brown-Sequard syndrome. MRI showed focal anterior …

Phenotypic variability of CMT4C in a French-Canadian kindred

Charcot‐Marie‐Tooth type 4C (CMT4C) is an autosomal recessive dysmyelinating neuropathy characterized by precocious and rapidly progressive scoliosis.

Autoimmune peripheral neuropathies

Peripheral nervous system axons and myelin have unique potential protein, proteolipid, and ganglioside antigenic determinants. Despite the existence of a blood-nerve barrier, both humoral and cellular immunity can be directed against peripheral axons and myelin. Molecular mimicry may be triggered at the systemic level, as was best demonstrated in the case of bacterial oligosaccharides. The classification of immune neuropathy has been expanded to take into account specific syndromes that share unique clinical, electrophysiological, prognostic and serological features. Guillain-Barré syndrome encompasses a classical syndrome of acute demyelinating polyradiculoneuropathy and many variants: axonal motor and sensory, axonal motor, Miller-Fisher, autonomic, and sensory. Similarly, chronic immune neuropathy is composed of classic chronic inflammatory demyelinating polyradiculoneuropathy and variants characterized as multifocal (motor or sensorimotor), sensory, distal symmetric, and syndromes associated with monoclonal gammopathy. Among putative biomarkers, myelin associated glycoprotein and several anti-ganglioside autoantibodies have shown statistically significant associations with specific neuropathic syndromes. Currently, the strongest biomarker associations are those linking Miller-Fisher syndrome with anti-GQ1b, multifocal motor neuropathy with anti-GM1, and distal acquired symmetric neuropathy with anti-MAG antibodies. Many other autoantibody associations have been proposed, but presently lack sufficient specificity and sensitivity to qualify as biomarkers. This field of research has contributed to the antigenic characterization of motor and sensory functional systems, as well as helping to define immune neuropathic syndromes with widely different clinical presentation, prognosis and response to therapy. Serologic biomarkers are likely to become even more relevant with the advent of new targeted forms of immunotherapy, such as monoclonal antibodies.

Case 138: Idiopathic Spinal Cord Herniation

A 66-year-old woman presented with numbness in the anteromedial aspect of her right thigh and difficulty with right leg movement for the past year. She did not have back pain or lower limb pain, nor did she have a history of relevant trauma. At the time of presentation, her arterial hypertension and osteoarthritis were being treated. She had a history of localized laryngeal amyloidosis, which was found at 30 years of age and treated with laser excision and tracheostomy. Physical examination revealed mild spasticity and impaired pain and temperature sensation in the right leg. She underwent magnetic resonance (MR) imaging, myelography, and postmyelography computed tomography (CT) of the thoracic spine.