Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is characterized by progressive muscle paralysis caused by degeneration of motor neurons in the primary motor cortex, corticospinal tracts, brainstem, and spinal cord. The age at onset for sporadic ALS is in average about 60 years. The majority of patients have a spinal form of the disease (with limb onset) and present focal muscle weakness and wasting. Spasticity usually develops in the atrophic limbs, affecting manual ability and gait. Patients with bulbar onset usually present with dysarthria and dysphagia for solids or liquids, and limb symptoms can develop within 1–2 years. Paralysis is progressive and leads to death due to respiratory failure within 2–3 years for bulbar onset cases and 3–5 years for limb onset cases.
The majority of ALS cases are sporadic, but 5–10 % are familial, and of these 20 % are due to mutations in the SOD1 gene (Table 85.1), 2–5 % in the TARDBP gene encoding the TAR DNA-binding protein 43 (TDP-43), and about 22 % of familial and 5 % of sporadic ALS are due to an expansion mutation in the C9orf72 gene.

Full text

371
C. Angelini, Genetic Neuromuscular Disorders: A Case-Based Approach,
DOI 10.1007/978-3-319-07500-6_85, © Springer International Publishing Switzerland 2014
Keywords Motor neuron disease • Neurogenic atrophy • Intronic expansion
mutation
Description
Amyotrophic lateral sclerosis (ALS) is characterized by progressive muscle paraly-
sis caused by degeneration of motor neurons in the primary motor cortex, cortico-
spinal tracts, brainstem, and spinal cord. The age at onset for sporadic ALS is in
average about 60 years. The majority of patients have a spinal form of the disease
(with limb onset) and present with focal muscle weakness and wasting. Spasticity
usually develops in the atrophic limbs, affecting manual ability and gait. Patients
with bulbar onset usually present with dysarthria and dysphagia for solids or liq-
uids, and limb symptoms can develop within 1–2 years. Paralysis is progressive and
leads to death due to respiratory failure within 2–3 years for bulbar onset cases and
3–5 years for limb onset cases.
The majority of ALS cases are sporadic, but 5–10 % are familial, and of these 20 %
are due to mutations in the SOD1 gene (Table
85.1 ), 2–5 % in the TARDBP gene
encoding the TAR DNA-binding protein 43 (TDP-43), and about 22 % of familial
and 5 % of sporadic ALS are due to an expansion mutation in the C9orf72 gene [ 1 ].
Chapter 85
Amyotrophic Lateral Sclerosis
Table 85.1 Genetic data Disease symbol ALS
Disease MIM # 105550
Gene symbol C9orf72
Gene MIM # 614260
Protein
Chromosome locus 9p21.2
Inheritance Autosomal dominant

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Case Report
This man had a dominant inheritance for frontotemporal dementia (mother and two
aunts). At age 51 years, he presented with dementia, lower motor neuron syndrome,
and bilateral gastrocnemius hypertrophy. He had a paraparetic and ataxic gait and
spastic hypertonia at lower limbs, deep tendon refl exes were brisk, and he had a thin
tongue with fasciculations also present in biceps. CK level was 1,116 U/L.
Laboratory Exams
Muscle biopsy performed at age 51 years showed numerous atrophic fi bers with
hyperchromic nuclei, hypertrophic fi bers with central nuclei, fi ber type grouping,
and atrophic fi bers of both fi ber types.
Molecular analysis showed a mutation in the c9orf72 gene.
Conclusion
The management of ALS is supportive, palliative, and multidisciplinary. Noninvasive
ventilation prolongs survival and improves quality of life. Riluzole is the only drug
that has been shown to extend survival.
In c9orf72 mutation, cognitive features are prominent and 5 % of cases exhibit
frontotemporal degeneration.
Key Points
• Both sporadic and familial ALS disorders are caused by c9ORF mutation.
• Frontotemporal dementia is also associated with c9ORF mutations, causing a
disease spectrum with extrapyramidal syndromes.
Reference
1. Rademakers R. C9orf72 repeat expansions in patients with ALS and FTD. Lancet Neurol.
2012;11(4):297–8.
85 Amyotrophic Lateral Sclerosis