Paula and Bobby
Parents of Lillie
Amyotrophic Lateral Sclerosis 1; ALS1
What is Amyotrophic Lateral Sclerosis 1; ALS1?
Amyotrophic Lateral Sclerosis 1; ALS1 is a rare disease. It is also known as ALS1 Amyotrophic Lateral Sclerosis 1, Autosomal Dominant Amyotrophic Lateral Sclerosis 1, Familial; Fals.
The mean age of onset in the familial type of motor neuron disease is about 45 years, and it therefore has an earlier age of onset than the more frequent sporadic types. The clinical picture can be secondary to lymphomas, plasma cell dyscrasias, insulin secreting tumors, HIV, hyperthyroidism, hyperparathyroidism, and heavy metal poisoning such as mercury (Scully et al., 1995). Note the case reported by Sasaki et al., (2000), with ubiquitin positive inclusions. Nine couples with conjugal ALS were reported from south east France (Corcia et al., 2003) suggesting both genetic and environmental factors are important.
It is suggested in many studies that about 5-10% of cases are genetic, and if they are, the likely mode of inheritance is autosomal dominant (note the report of conjugal ALS in two couples, Camu et al., 1994). Minor sensory signs might occur in about 20% of cases, and this is not surprising as the posterior columns as well as the spino-cerebellar tracts are commonly found to be affected at post-mortem. Extrapyramidal involvement (retropulsion) was described by Desai and Swash (1999). This entity includes primary lateral sclerosis as there have been patients diagnosed as such, who, after many years, develop ALS. A large study of 20 patients (Le Forestier et al., 2001) also concluded that primary lateral sclerosis represented one end of the continuous spectrum of ALS. Both primary lateral sclerosis and ALS are occasionally associated with IgM paraproteinemia (Desai and Swash, 1999). Twin studies have shown rather low concordance rates for monozygotic twins. 9.5% in the Graham et al., (1997) study. The heritability estimate in that study gave a wide range of between 38-85%. Fang et al., (2009) found that risks to sibs and offspring were 10 times greater than their control group.
There is still argument about concordance within families for age of onset and duration (age of death), and although concordance might occur, there are sufficient exceptions not to be able to use this for counselling purposes. In a family reported by Ikeda et al., (1995), the age of onset varied between 6 and 55, and there was one mutation carrier (there was a novel point mutation in the Cu/Zn SOD gene) who was clinically well at 59. Dementia is an unusual manifestation (7%). Risks to first degree relatives when the index case is sporadic, is 1 in 85 at 20 years, dropping to less than 1 in 1000 at 80 years (James et al., 1995). There is one report of malignant hyperthermia in this condition (Monsieurs et al., 1997). Some patients with Kennedy syndrome can be misdiagnosed as having ALS and this should be genetically excluded in atypical cases (Parboosingh et al., 1997).
One late-onset sporadic case has been shown to be homozygous for a deletion at the spinal muscular atrophy types I, II, and III, locus, but this must be unusual (Jackson et al., 1996). However, a homozygous deletion of SMN2 might act as a prognostic factor and phenotype modifier (Veldink et al., 2001). This was not supported by the study of Gamez et al., (2002). In the rare families in which ALS and SMA coexist (Corcia et al., 2002) at least 2 copies of SMN1 were present in those with ALS.. In the study by Echaniz-Laguna et al., (2002) 36% of patients with ALS had homozygous deletions vrs 5% of the population.
One patient with MND has been found to have a COX I microdeletion (Comi et al., 1998) and ALS, as a complex interaction of genetic factors, oxidative stress and imbalance of the glutamanergic exitatory control of motor neurons, is discussed by Shaw (2000).
The issues surrounding presymptomatic testing are discussed by Fanos et al., (2004). There are parallels with Huntington's chorea testing.The complex genetics of ALS is reviewed by Kunst (2004).
* This information is courtesy of the L M D.
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What gene changes cause Amyotrophic Lateral Sclerosis 1; ALS1?
The syndrome is inherited in the following inheritance pattern/s:
Autosomal Dominant - In the case of autosomal dominant inheritance, just one parent is the carrier of the gene mutation, and they have a 50% chance of passing it onto each of their children. Syndromes inherited in an autosomal dominant inheritance are caused by just one copy of the gene mutation.
Sporadic - In some cases, a genetic syndrome may be the result of a de-novo mutation and the first case in a family. In this case, this is a new gene mutation that occurs during the reproductive process.
In some cases, a genetic syndrome may be the result of a de-novo mutation and the first case in a family. In this case, this is a new gene mutation that occurs during the reproductive process.
OMIM Number - 105400 (please check the OMIM page for updated information)
The syndrome can be caused by mutations in the following gene/s location/s:
BCL2L1 - 20q11.21
SHC1 - 1q21.3
JAK3 - 19p13.11
CREBBP - 16p13.3
FGF6 - 12p13.32
CTSD - 11p15.5
TLE3 - 15q23
TMSB4X - Xp22.2
SOD1 - 21q22.11
OTOG - 11p15.1
PDGFA - 7p22.3
TIAM1 - 21q22.11
SELPLG - 12q24.11
JUND - 19p13.11
CALB2 - 16q22.2
TNF - 6p21.33
SNAI1 - 20q13.13
DCTN1 - 2p13.1
GSX2 - 4q12
CNTF - 11q12.1
RXRA - 9q34.2
GFAP - 17q21.31
GABRA1 - 5q34
VIM - 10p13
GRIA3 - Xq25
CD7 - 17q25.3
GBX2 - 2q37.2
PRPH - 12q13.12
PENK - 8q12.1
FOS - 14q24.3
KIF3C - 2p23.3
BSG - 19p13.3
GDI1 - Xq28
NEFH - 22q12.2
XIAP - Xq25
CASP1 - 11q22.3
CD68 - 17p13.1
PON1 - 7q21.3
SIX2 - 2p21
WNT7A - 3p25.1
CLU - 8p21.1
CST3 - 20p11.21
LDLR - 19p13.2
FMO1 - 1q24.3
LAT - 16p11.2
HSF1 - 8q24.3
What are the main symptoms of Amyotrophic Lateral Sclerosis 1; ALS1?
The typical symptoms of the syndrome are:
Fasciculations, Degeneration of the lateral corticospinal tracts, Degeneration of anterior horn cells, Muscle weakness, Muscle spasm, Hyperreflexia, Amyotrophic lateral sclerosis, Skeletal muscle atrophy, Autosomal recessive inheritance, Autosomal dominant inheritance, Heterogeneous, Spasticity, Pseudobulbar paralysis, Sleep apnea
How does someone get tested for Amyotrophic Lateral Sclerosis 1; ALS1?
The initial testing for Amyotrophic Lateral Sclerosis 1; ALS1 can begin with facial genetic analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the type of genetic testing needed. A consultation with a genetic counselor and then a geneticist will follow.
Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.
What is FDNA Telehealth?
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