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Amyotrophic Lateral Sclerosis: Diagnostic stategy and overview

Klinische Symptomatik

Diagnostic Strategy

  1. C9orf72 repeat length analysis
  2. Multi-gene panel analysis

Should no multi-gene panel analysis be possible, the following alternative single-gene analyses should be considered according to the frequency of detected mutations:

  • SOD1
  • FUS, TARDBP; if applicable, other genes (as indicated by clinical phenotype)

Clinical Features

Amyotrophic lateral sclerosis (ALS) is one of the most common neurodegenerative disorders with progressive motor neuron loss in the central and peripheral nervous systems resulting in progressive paralysis of the skeletal muscles.

Approximately 10 - 15 % of cases run in families. Almost indistinguishable from sporadic ALS clinically, familial ALS (FALS) manifests as an age-dependent, usually autosomal dominant disorder with an average age of onset of about 45 years. Development of FALS after the age of 60 is rare.


Approximately 10 % of cases of ALS run in families. Familial ALS (FALS) often follows an autosomal dominant pattern of inheritance; however, rare cases of autosomal recessive and X-linked inheritance have also been described. The disease is genetically heterogeneous:

  • C9orf72 (chromosome 9p21): The identification of a hexanucleotide repeat expansion in this gene recently clarified the cause of amyotrophic lateral sclerosis with frontotemporal dementia (ALS-FTD). This repeat expansion was found to be the most common cause of familial (46 %) and sporadic (21 %) cases of ALS in Finland and was identified in over 30 % of European patients with familial ALS (Renton AE et al., Neuron 2011).
  • SOD1 (copper-zinc superoxide dismutase 1; chromosome 21q22; ALS1): Mutations are found in approx. 12-20 % of families with FALS and in approx. 3 % of patients with sporadic ALS. Mutations in SOD1 follow an autosomal dominant pattern of inheritance.
  • TARDBP (TAR DNA binding protein; chromosome1p36.2; ALS10): Mutations account for approx. 4 % of all cases of FALS and follow an autosomal dominant pattern of inheritance.
  • FUS (fused in sarcoma; chromosome 16p11.2; ALS6): Mutations account for approx. 4 % of all cases of FALS and follow an autosomal dominant pattern of inheritance.

There are also a number of additional genes and gene loci associated with ALS which are responsible for only a small proportion of cases of FALS. These include:

  • FIG4 (SAC domain-containing inositol phosphatase 3, SAC3; chromosome 6q21, ALS11): Mutations in this gene were originally identified in patients with autosomal recessive hereditary neuropathy (CMT4J) and subsequently identified as autosomal dominantly inherited mutations in 1-2 % of a mixed FALS/SALS collective.
  • ANG (angiogenin; chromosome 14q11; ALS9): Mutations have been described in less than 1 % of all familial and sporadic cases of ALS. Patients with ANG mutations often initially present with bulbar symptoms. Mutations in ANG1 follow an autosomal dominant pattern of inheritance. Some mutations have also been found in healthy control subjects and may possibly represent a risk factor in certain ethnic populations.
  • SETX (senataxin; chromosome 9q34.13; ALS4): Autosomal dominant mutations in SETX lead to progressive distal muscle weakness and muscular atrophy beginning in a patient’s teen years and accompanied by signs of 1st motor neuron impairment but no bulbar symptoms. Autosomal recessive mutations in SETX cause ataxia with oculomotor apraxia type 2 (AOA2)

  • VCP (valosin-containing protein; chromosome 9p13.3; ALS14): Mutations in the gene VCP were originally described in an Italian family with an autosomal dominant form of inherited ALS with signs of 1st and 2nd motor neuron impairment. Mutations in VCP have also been identified in patients with inclusion body myopathy with Paget disease and frontotemporal dementia (IBMPFD).

  • CHCHD10 (coiled-coil-helix-coiled-coil-helix domain-containing protein 10; chromosome 22q11.23; FTD/ALS2): Mutations in this gene have been identified in families with frontotemporal dementia and/or ALS. Heterozygous mutations in CHCHD10 have also been described in a case of Jokela type spinal muscular atrophy (SMAJ) and in a family with autosomal dominant isolated mitochondrial myopathy.

  • ALS2 (alsin; chromosome 2q33.1; ALS2): Autosomal recessive mutations in ALS2 lead to childhood-onset (average age of onset is 6.5 years) spastic paresis, spasticity of the facial musculature, uncontrollable laughing, spastic dysarthria, spastic gait, and bladder and sensory disorders. Patients with infantile-onset ascending spastic paralysis (IAHSP) usually develop primary lateral sclerosis (JPLS). However, families with 2nd motor neuron involvement in the form of ALS with dominating impairment of the 1st motor neuron have also been reported.

  • OPTN (optineurin; chromosome 10p13; ALS12): Mutations in this gene result in autosomal recessive inherited ALS with an age of onset between 20 and 60 years of age and, in most cases, slow progression.

  • UBQLN2 (ubiquilin 2; chromosome Xp11.21; ALS15): Mutations in the gene UBQLN2 are inherited in an X-linked dominant manner and cause ALS with or without frontotemporal dementia.

Differential Diagnostics

Especially important in terms of differential diagnosis are hereditary distal motor neuron diseases (see dHMN; genes BSCL2, DCTN1, GARS, HSPB8, and SETX), which cannot always be clearly defined by clinical features alone. Depending on the patient’s age, sole participation of the 2nd motor neuron could indicate SMA type IV (ALS8, VAPB gene) or, in men, Kennedy type spinal and bulbar muscular atrophy (SBMA, AR gene). Sole or predominant involvement of the 1st motor neuron may indicate primary lateral sclerosis (PLS or Alsin, juvenile form, ALS2, ALS2 gene) and FIG4 (ALS11) or, in conjunction with spastic paresis of the lower extremities, hereditary spastic paraplegia. In recent years, clinical overlap with other central neurodegenerative disorders (particularly frontal dementia and Parkinsonism) has become apparent; analysis of the recently identified genetic mutation on chromosome 9p21 (C9orf72) plays the most significant role in such cases.


Approximately 1 : 25 000 in the European population


Identification of the disease-causing mutations in affected families; predictive diagnostics in affected families only subsequent to genetic counselling; sporadic cases for detection of a possible de novo mutation.

Methodik Next Generation Sequencing (NGS)

Parallele Sequenzierung mehrerer Gene

Material 2-4 ml EDTA-Blut
3-6 Wochen


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