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Infantile-onset ascending hereditary spastic paralysis(IAHSP)

MedGen UID:
419413
Concept ID:
C2931441
Disease or Syndrome
Synonyms: Autosomal Recessive Juvenile Amyotrophic Lateral Sclerosis; IAHSP; Spastic paralysis, infantile onset ascending
SNOMED CT: Infantile-onset ascending hereditary spastic paralysis (703543005); IAHSP - infantile onset ascending hereditary spastic paralysis (703543005); Infantile ascending hereditary spastic paralysis (703543005)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): ALS2 (2q33.1)
 
Monarch Initiative: MONDO:0011797
OMIM®: 607225
Orphanet: ORPHA293168

Disease characteristics

Excerpted from the GeneReview: ALS2-Related Disorder
ALS2-related disorder involves retrograde degeneration of the upper motor neurons of the pyramidal tracts and comprises a clinical continuum of the following three phenotypes: Infantile ascending hereditary spastic paraplegia (IAHSP), characterized by onset of spasticity with increased reflexes and sustained clonus of the lower limbs within the first two years of life, progressive weakness and spasticity of the upper limbs by age seven to eight years, and wheelchair dependence in the second decade with progression toward severe spastic tetraparesis and a pseudobulbar syndrome caused by progressive cranial nerve involvement. Juvenile primary lateral sclerosis (JPLS), characterized by upper motor neuron findings of pseudobulbar palsy and spastic quadriplegia without dementia or cerebellar, extrapyramidal, or sensory signs. Juvenile amyotrophic lateral sclerosis (JALS or ALS2), characterized by onset between ages three and 20 years. All affected individuals show a spastic pseudobulbar syndrome (spasticity of speech and swallowing) together with spastic paraplegia. Some individuals are bedridden by age 12 to 50 years. [from GeneReviews]
Authors:
Richard W Orrell   view full author information

Additional descriptions

From OMIM
Infantile-onset ascending hereditary spastic paralysis (IAHSP) is an autosomal recessive neurodegenerative disorder characterized by onset in the first years of life of progressive upper and lower motor neuron degeneration resulting in loss of ability to walk in childhood. It initially affects the lower limbs and then ascends to the upper limbs and bulbar muscles, causing dysarthria and dysphagia. Cognition is unaffected (summary by Wakil et al., 2014).  http://www.omim.org/entry/607225
From MedlinePlus Genetics
A condition called juvenile primary lateral sclerosis shares many of the features of infantile-onset ascending hereditary spastic paralysis. Both conditions have the same genetic cause and significantly impair movement beginning in childhood; however, the pattern of nerve degeneration is different. Because of their similarities, these conditions are sometimes considered the same disorder.

Affected infants are typically normal at birth, then within the first 2 years of life, the initial symptoms of infantile-onset ascending hereditary spastic paralysis appear. Early symptoms include exaggerated reflexes (hyperreflexia) and recurrent muscle spasms in the legs. As the condition progresses, affected children develop abnormal tightness and stiffness in the leg muscles and weakness in the legs and arms. Over time, muscle weakness and stiffness travels up (ascends) the body from the legs to the head and neck. Muscles in the head and neck usually weaken during adolescence; symptoms include slow eye movements and difficulty with speech and swallowing. Affected individuals may lose the ability to speak (anarthria). The leg and arm muscle weakness can become so severe as to lead to paralysis; as a result affected individuals require wheelchair assistance by late childhood or early adolescence. Intelligence is not affected in this condition.

Infantile-onset ascending hereditary spastic paralysis is one of a group of genetic disorders known as hereditary spastic paraplegias. These disorders are characterized by progressive muscle stiffness (spasticity) and eventual paralysis of the lower limbs (paraplegia). The spasticity and paraplegia result from degeneration (atrophy) of motor neurons, which are specialized nerve cells in the brain and spinal cord that control muscle movement. Hereditary spastic paraplegias are divided into two types: pure and complicated. The pure types involve only the lower limbs, while the complicated types involve additional areas of the nervous system, affecting the upper limbs and other areas of the body. Infantile-onset ascending hereditary spastic paralysis starts as a pure hereditary spastic paraplegia, with spasticity and weakness in the legs only, but as the disorder progresses, the muscles in the arms, neck, and head become involved and features of the disorder are more characteristic of the complicated type.  https://medlineplus.gov/genetics/condition/infantile-onset-ascending-hereditary-spastic-paralysis

Clinical features

From HPO
Urinary incontinence
MedGen UID:
22579
Concept ID:
C0042024
Finding
Loss of the ability to control the urinary bladder leading to involuntary urination.
Pes cavus
MedGen UID:
675590
Concept ID:
C0728829
Congenital Abnormality
An increase in height of the medial longitudinal arch of the foot that does not flatten on weight bearing (i.e., a distinctly hollow form of the sole of the foot when it is bearing weight).
Dysphagia
MedGen UID:
41440
Concept ID:
C0011168
Disease or Syndrome
Difficulty in swallowing.
Dysarthria
MedGen UID:
8510
Concept ID:
C0013362
Mental or Behavioral Dysfunction
Dysarthric speech is a general description referring to a neurological speech disorder characterized by poor articulation. Depending on the involved neurological structures, dysarthria may be further classified as spastic, flaccid, ataxic, hyperkinetic and hypokinetic, or mixed.
Tetraplegia
MedGen UID:
19617
Concept ID:
C0034372
Disease or Syndrome
Paralysis of all four limbs, and trunk of the body below the level of an associated injury to the spinal cord. The etiology of quadriplegia is similar to that of paraplegia except that the lesion is in the cervical spinal cord rather than in the thoracic or lumbar segments of the spinal cord.
Babinski sign
MedGen UID:
19708
Concept ID:
C0034935
Finding
Upturning of the big toe (and sometimes fanning of the other toes) in response to stimulation of the sole of the foot. If the Babinski sign is present it can indicate damage to the corticospinal tract.
Spastic paraplegia
MedGen UID:
20882
Concept ID:
C0037772
Disease or Syndrome
Spasticity and weakness of the leg and hip muscles.
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Hyperreflexia is the presence of hyperactive stretch reflexes of the muscles.
Anarthria
MedGen UID:
68604
Concept ID:
C0234517
Disease or Syndrome
A defect in the motor ability that enables speech.
Spastic tetraplegia
MedGen UID:
98433
Concept ID:
C0426970
Disease or Syndrome
Spastic paralysis affecting all four limbs.
Motor delay
MedGen UID:
381392
Concept ID:
C1854301
Finding
A type of Developmental delay characterized by a delay in acquiring motor skills.
Abnormal lower motor neuron morphology
MedGen UID:
356272
Concept ID:
C1865412
Finding
Any structural anomaly of the lower motor neuron.
Abnormal corticospinal tract morphology
MedGen UID:
893081
Concept ID:
C4025704
Anatomical Abnormality
Abnormality of the corticospinal tract, which is the chief element of the pyramidal system (the principle motor tract) and is the only direct connection between the cerebrum and the spinal cord.
Scoliosis
MedGen UID:
11348
Concept ID:
C0036439
Disease or Syndrome
The presence of an abnormal lateral curvature of the spine.
Muscle weakness
MedGen UID:
57735
Concept ID:
C0151786
Finding
Reduced strength of muscles.
Achilles tendon contracture
MedGen UID:
98052
Concept ID:
C0410264
Anatomical Abnormality
A contracture of the Achilles tendon.
Impaired mastication
MedGen UID:
66779
Concept ID:
C0239043
Finding
An abnormal reduction in the ability to masticate (chew), i.e., in the ability to crush and ground food in preparation for swallowing.
Abnormality of the face
MedGen UID:
871375
Concept ID:
C4025871
Anatomical Abnormality
An abnormality of the face.
Slow saccadic eye movements
MedGen UID:
232942
Concept ID:
C1321329
Finding
An abnormally slow velocity of the saccadic eye movements.
Abnormality of the eye
MedGen UID:
1370071
Concept ID:
C4316870
Anatomical Abnormality
Any abnormality of the eye, including location, spacing, and intraocular abnormalities.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVInfantile-onset ascending hereditary spastic paralysis
Follow this link to review classifications for Infantile-onset ascending hereditary spastic paralysis in Orphanet.

Professional guidelines

PubMed

Rossi Sebastiano M, Ermondi G, Sato K, Otomo A, Hadano S, Caron G
Molecules 2022 Oct 19;27(20) doi: 10.3390/molecules27207063. PMID: 36296656Free PMC Article

Recent clinical studies

Etiology

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Diagnosis

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Prognosis

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Eltoum A, O'Rourke D, Sharif F
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Helal M, Mazaheri N, Shalbafan B, Malamiri RA, Dilaver N, Buchert R, Mohammadiasl J, Golchin N, Sedaghat A, Mehrjardi MYV, Haack TB, Riess O, Chung WK, Galehdari H, Shariati G, Maroofian R
Neurol Sci 2018 Nov;39(11):1917-1925. Epub 2018 Aug 21 doi: 10.1007/s10072-018-3526-8. PMID: 30128655
Racis L, Tessa A, Pugliatti M, Storti E, Agnetti V, Santorelli FM
Eur J Paediatr Neurol 2014 Mar;18(2):235-9. Epub 2013 Oct 9 doi: 10.1016/j.ejpn.2013.09.009. PMID: 24144828
Hadano S, Kunita R, Otomo A, Suzuki-Utsunomiya K, Ikeda JE
Neurochem Int 2007 Jul-Sep;51(2-4):74-84. Epub 2007 May 4 doi: 10.1016/j.neuint.2007.04.010. PMID: 17566607

Clinical prediction guides

Zhang Q, Yang Q, Luo J, Zhou X, Yi S, Tan S, Qin Z
BMC Med Genomics 2024 Jan 31;17(1):44. doi: 10.1186/s12920-024-01805-x. PMID: 38297306Free PMC Article
Racis L, Tessa A, Pugliatti M, Storti E, Agnetti V, Santorelli FM
Eur J Paediatr Neurol 2014 Mar;18(2):235-9. Epub 2013 Oct 9 doi: 10.1016/j.ejpn.2013.09.009. PMID: 24144828
Hadano S, Kunita R, Otomo A, Suzuki-Utsunomiya K, Ikeda JE
Neurochem Int 2007 Jul-Sep;51(2-4):74-84. Epub 2007 May 4 doi: 10.1016/j.neuint.2007.04.010. PMID: 17566607
Eymard-Pierre E, Lesca G, Dollet S, Santorelli FM, di Capua M, Bertini E, Boespflug-Tanguy O
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