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Familial amyotrophic lateral sclerosis (FALS) is recognised as a heterogeneous syndrome with mutations in the Cu/Zn superoxide dismutase (SOD1) gene being the most frequently identified cause of ALS. Interfamily and intrafamily phenotypic variability have been associated with some SOD1 mutations but not with other mutations.1 2 We prospectively screened sporadic ALS and FALS patients from Switzerland for SOD1 mutations and followed their clinical course.
With written informed consent and approval by the local ethical review boards, blood was drawn from 257 patients and from 245 Swiss blood donors matched for ethnicity, age and gender. Forty-seven of the patients had one or more affected blood relatives within three generations and were classified as FALS. SOD1 analysis was performed in Sweden as described.1
Nine patients from seven unrelated families carried a SOD1 mutation (table 1), including three novel mutations (V5L, L144F (TTG→TTT) and E78insSI (c.240-7T→G)). Among the controls, a single individual was found to be heterozygous for a silent mutation A140A.
Selected phenotypic depictions of patients with SOD1 mutations
In 1962, at the age of 28 years, the patient (2a) noticed weakness in her legs and was diagnosed as having Friedreich ataxia in the same year and spinal muscular atrophy 5 years later. She became a wheelchair user 28 years after symptom onset. A percutaneous endoscopic gastrostomy tube was inserted and non-invasive ventilation started 41 years after symptom onset. Two years later, reflexes in her arms were pathologically brisk and absent in her legs. Fasciculations were present in her legs and left arm. Wasting and weakness were moderate in proximal muscles and prominent in distal muscles. Cerebellar ataxia was present in her arms. Her speech was weak and dysphonic with mild dysarthria. Her tongue was slightly atrophic with few fasciculations and the masseter reflex was brisk. The patient died in 2006, 44 years after symptom onset. Her cousin (2b) initially developed gait instability followed by weakness in both hands. Six months after symptom onset, reflexes in his arms were exaggerated, weak to absent in his legs with bilateral Babinski signs. Moderate weakness was present in distal and proximal hand and leg muscles. He had slow tongue movements, a nasal voice but no dysarthria. His tongue showed no atrophy, but rare fasciculations. The patient died of respiratory failure 5.5 years after symptom onset. In the previous generation, three family members had died of ALS with disease durations of more than 5 years. The female patient's father died at the age of 82 years and the male patient's father died at the age of 70 years.
This 43-year-old woman originated from the Balkans. First symptoms were left leg weakness and wasting. Dysphagia developed 4 years after symptom onset. Shortly before death, her voice was dysphonic and high pitched without dysarthria, wasting or fasciculations of her tongue. Weakness was severe in distal hand muscles and moderate in proximal leg muscles. Reflexes were absent but the right brachioradialis reflex had spread to the finger flexors. The patient declined percutaneous endoscopic gastrostomy and non-invasive ventilation and died 4.5 years after symptom onset. Her mother had died of ALS at the age of 75 years. Two aunts on her mother's side had been diagnosed with multiple sclerosis but had died within 5 years after the diagnosis.
This 36-year-old woman's first symptoms were falls and the inability to stand on her left toes. A cousin of her grandfather had died of ALS. Fourteen months later, moderate flaccid weakness was present in her left leg and hip muscles. No fasciculations were visible. Tendon reflexes in her arms were brisk, absent in her legs. Currently, 6 years after symptom onset, the patient exhibits paraplegia, mild-to-moderate weakness in her arms and moderate nasality of her voice. The patient's father, aged 73 years, carries the V5L mutation but has no symptoms or signs of ALS. Her paternal aunt first experienced falls at the age of 70 years. Thirty-two months after symptom onset, she presented with severe left leg spasticity, exaggerated tendon reflexes and severe right hand and mild left hand weakness. Mild wasting and fasciculations of her tongue were also present. She died 46 months after symptom onset.
This 42-year-old woman first noticed tiredness and cramps in her left leg and fasciculations in her legs and arms. Seven months later, proximal weakness and moderate wasting of her left thigh, brisk reflexes in her legs and exaggerated reflexes in her arms were present. The hands and the bulbar region were affected 6 and 7 months later, respectively. She died of respiratory failure 19 months after symptom onset. Her mother, a cousin and an aunt had died of ALS. Survival varied between 1 and 5 years.
The most striking patient in this study was patient 2a with a 44-year survival, the second longest survival on record for a confirmed case of ALS.3 The L144F (TTG→TTT) mutation co-segregated with ALS in the family. Variability of age of onset ranged from 28 to 70 years in this family. A similar extreme phenotypic variability has been reported in a Japanese family (I104F mutation) with the age of onset varying between 6 and 55 years and disease duration between 3 and 38 years.2 Variability of age of onset and survival is common in patients with the other L144F mutation (TTG→TTC).4 Remarkably, all our L144F patients shared sparing of the tongue. Although speech was either dysphonic or nasal, dysarthria and tongue wasting were clinically absent. Neither our patients nor any of the other 26 reported patients carrying the L144F mutation had bulbar onset.4
The index patient carrying the V5L mutation exhibits a slowly progressive phenotype of the ‘flail leg variant’. While variability in the age of onset is great in this family (36–70 years), penetrance may be incomplete since her father, aged 70 years, and other members carrying the V5L mutation do not have any symptoms or signs of ALS.
In a Swiss family with high penetrance for FALS, we found an intronic splice site mutation (c.240-7T→G or E78insSI) resulting in the insertion of two novel amino acids serine and isoleucine between exons 3 and 4.5 Clinically, the phenotype may be associated with rapid progression but otherwise is no different from patients with most other SOD1 gene mutations.
We are indebted to the patients and their families for their participation in this project. We are thankful to Dr Bont, Winterthur Switzerland for collaborating on this project.
Funding This project has been generously supported by the Swiss ALS Foundation, Swedish Brain Research Foundation, Bertil Hållsten's Research Foundation, the Swedish Brain Power Consortium, the Swedish Science Council and the Swedish Association for the Neurologically Disabled.
Competing interests None.
Patient consent Obtained.
Ethics approval All local IRBs approved the study.
Provenance and peer review Not commissioned; externally peer reviewed.
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