Göran Solders

Familial insensitivity to pain (HSAN V) and a mutation in the NGFB gene. A neurophysiological and pathological study.

We have studied a large Swedish family with a mutation in the nerve growth factor beta (NGFB) gene causing insensitivity to deep pain without anhidrosis (hereditary sensory and autonomic neuropathy, type V; HSAN V). Painfree joint destruction and fractures were common. Peripheral nerve conduction was normal, but temperature thresholds were increased. Sural nerve biopsies showed a moderate loss of Aδ fibers and a severe reduction of C fibers. The three most severely affected cases were all born to consanguineous parents, and were homozygotes for the causal genetic mutation. Treatment of these patients is discussed. Muscle Nerve, 2004

Long-term consequences of domino liver transplantation using familial amyloidotic polyneuropathy grafts

Domino liver transplantation (DLT) using grafts from patients with familial amyloidotic polyneuropathy (FAP) is an established procedure at many transplantation centers. However, data evaluating the long‐term outcome of DLT are limited. The aim of the present study was to analyze the risk of de novo polyneuropathy, possibly because of amyloidosis, and the patient survival after DLT. At our department, 28 DLT using FAP grafts were conducted between January 1997 and December 2005. One patient was twice subjected to DLT. Postoperative neurological monitoring of peripheral nerve function was performed with electroneurography (ENeG) in 20 cases. An ENeG index based on 12 parameters was calculated and correlated to age and/or height. Three patients developed ENeG signs of polyneuropathy 2–5 years after the DLT, but with no clinical symptoms. The 1‐, 3‐ and 5‐year actuarial patient survival in hepatocellular carcinoma (HCC) patients (n = 12) and non‐HCC patients (n = 15) was 67%, 15%, 15% and 93%, 93%, 80%, respectively (P = 0.001). Development of impaired nerve conduction in a proportion of patients may indicate that de novo amyloidosis occurs earlier than previously expected. Survival after DLT was excellent except in patients with advanced HCC.

Orthopedic aspects of familial insensitivity to pain due to a novel nerve growth factor beta mutation.

Background Congenital insensitivity to pain is a rare hereditary sensory neuropathy Patients We present 6 patients from a family with a mutation in the nerve growth factor beta gene (NGFB) Results 3 patients were homozygous with a mutilating arthropathy starting early in life, and 3 patients were presumably heterozygous with a milder course starting in adulthood. All patients had normal mental abilities. In addition to absence of deep pain, the patients had impaired temperature sensation, but no autonomic deficiency. Sural nerve biopsies showed a moderate loss of A-δfibres and a severe reduction in C fibers. Clinically, the disorder most often affected the lower extremities, with an insidious progressive joint swelling or a painless fracture, but the spine could also be involved with gross and unstable spondylolisthesis. Fracture healing was uneventful, but the arthropathy was progressive, eventually resulting in gross deformity and instability. When treating patients with congenital disorders such as this one, it is important to consider the slowly progressive nature of the disorder, and the orthopedic operations should therefore be planned from a long-term standpoint. Arthrodesis, limb lengthening and spinal decompression or fusion are the only elective procedures that seem reasonable. Fitting of orthosis for joint protection is also demanding. To delay the development of neuropathic arthropathy, patient education is essential but difficult in the very young Interpretation The different expression between homo- and heterozygous subjects and the central role of nerve growth factor make this disease an interesting model system for studies of disease mechanisms and the molecular background to pain.

A novel NGFB point mutation, a phenotype study of heterozygous patients

Objective: A family with neurological findings similar to hereditary sensory and autonomic neuropathy type V having a point mutation in the nerve growth factor beta (NGFB) gene was recently described. The homozygous genotype gives disabling symptoms. The purpose of the present study was to evaluate the symptoms in heterozygous patients. Methods: 26 patients heterozygous for the NGFB mutation (12 men, mean age 50 (13–90) years) were examined clinically and answered a health status questionnaire, including the Michigan Neuropathy Screening Instrument (MNSI). 28 relatives (15 men, mean age 44 (15–86) years) without the mutation served as controls in the clinical examination part. 23 of the heterozygotes were examined neurophysiologically and six heterozygous patients underwent a sural nerve biopsy. Results: The heterozygous phenotype ranged from eight patients with Charcot arthropathy starting in adult age and associated with variable symptoms of neuropathy but without complete insensitivity to pain, anhidrosis or mental retardation, to 10 symptom free patients. There was no difference in MNSI between the young heterozygous cases (<55 years old) and the controls. Six of 23 heterozygous patients had impaired cutaneous thermal perception and 11 of 23 had signs of carpal tunnel syndrome. Sural nerve biopsies showed a moderate reduction of both small myelinated (Aδ) and unmyelinated (C) fibres. No apparent correlation of small fibre reduction to symptoms was found. Conclusions: The NGFB mutation in its heterozygous form results in a milder disease than in homozygotes, with a variable clinical picture, ranging from asymptomatic cases to those with Charcot arthropathy appearing in adult age. Particularly age, but perhaps lifestyle factors also, may influence the development of clinical polyneuropathy.

Late-onset limb-girdle muscular dystrophy caused by GMPPB mutations

Mutations in GMPPB gene have been reported in patients with early-onset disease ranging from severe congenital muscular dystrophies to limb-girdle muscular dystrophy (LGMD) with mental retardation. More recently mutations in GMPPB have been identified with congenital myasthenic syndromes as well as milder phenotypes. We report two unrelated cases with LGMD that underwent clinical, histopathological and genetic studies. In both cases, we found identical compound heterozygous GMPPB mutations c.79G>C p.D27H and c.859C>T p.R287W, leading to a glycosylation defect of alpha-dystroglycan. The onset of muscle weakness was 30-40 years and the progression rate mild to moderate. Case 2 became wheelchair-bound at the age of 60. No cognitive or behavioral symptoms were noted. These cases provide further evidence that GMPPB mutations can also cause late-onset recessive LGMD with milder phenotypes than previously reported, and thus should be considered in the differential diagnosis of patients with adult-onset muscular dystrophies.

G.P.255

Pompe disease (acid maltase deficiency or glycogen storage disease type II) is an autosomal-recessive inherited and potentially treatable metabolic myopathy with heterogeneous clinical presentations and with considerable overlap of signs and symptoms with other neuromuscular disorders. According to previous reports, patients with Pompe disease have often been incorrectly diagnosed as limb-girdle muscular dystrophy (LGMD). To diagnose both entities is challenging and a diagnostic delay of several years is common. The frequency of misdiagnosis is unknown. Epidemiologic studies on Pompe disease have not been done in the nordic countries. This is the first, registry-based, study on epidemiology of Pompe disease in Sweden. First, we identified all patients with Pompe disease by validating retrospectively the diagnosis using the medical records of individuals with the unspecified diagnosis code E74.0 (glycogen storage diseases) according to the International Classification of Diseases version 10 (ICD-10). Beyond this, we selected from the National Patient Registry all in-and outpatients in Sweden with genetically unclassified LGMD and limb-girdle muscle weakness and then screened for Pompe disease by enzyme analysis on dried blood spots. Hereby, we report the preliminary results of the screening study and data on the prevalence of Pompe disease in Sweden.

Epidemiology and Screening for Pompe Disease in Sweden

Pompe disease (PD; acid maltase defi ciency or glycogen storage disease type II) is an autosomal recessive inherited, potentially treatable metabolic myopathy with heterogeneous clinical presentations and with considerable overlap of signs and symptoms found in other neuromuscular disorders. According to previous reports, patients with PD have been incorrectly diagnosed for several years as limb–girdle muscular dystrophies (LGMDs). To diagnose both entities is challenging, and a diagnostic delay of several years seems to be common. The frequency of misdiagnosis is unknown. No epidemiologic studies have been carried out on PD in the nordic countries.

G.P.254

There have been only a few epidemiological studies on muscular dystrophies in the nordic countries, mainly based on manually collected data from specialized laboratories. The Swedish National Patient Registry at the National Board of Health and Welfare and at the Central Bureau of Statistics are particularly suitable to investigate epidemiologically these rare diseases. We are conducting the first Swedish nationwide, registry-based, descriptive study on the epidemiology of limb-girdle muscular dystrophies (LGMDs) with the aim to clarify the incidence, prevalence, mortality and prognosis of different LGMD-subtypes and to identify any predictors for (mis) diagnosis. Hereby, we present the preliminary results from this study, covering at least 50% of the Swedish population. This register study will be the basis for further studies, especially for drug trials and additional diagnostical interventions.