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MASA syndrome(SPG1)

MedGen UID:
162894
Concept ID:
C0795953
Disease or Syndrome
Synonyms: Adducted thumb with mental retardation; Clasped thumb and mental retardation; Crash syndrome; Gareis-Mason syndrome; MASA Syndrome (Mental Retardation, Adducted Thumbs, Shuffling Gait, and Aphasia); Mental Retardation Aphasia Shuffling Gait Adducted Thumbs (MASA); MENTAL RETARDATION, APHASIA, SHUFFLING GAIT, AND ADDUCTED THUMBS; Spastic paraplegia 1; SPASTIC PARAPLEGIA 1, X-LINKED; SPG1; Thumb congenital clasped with mental retardation
SNOMED CT: MASA syndrome (838441009); MASA (mental retardation, adducted thumbs, shuffling gait, aphasia) syndrome (838441009); Intellectual disability, aphasia, shuffling gait, adducted thumbs syndrome (838441009); Mental retardation, adducted thumbs, shuffling gait, aphasia syndrome (838441009)
Modes of inheritance:
X-linked recessive inheritance
MedGen UID:
375779
Concept ID:
C1845977
Finding
Source: Orphanet
A mode of inheritance that is observed for recessive traits related to a gene encoded on the X chromosome. In the context of medical genetics, X-linked recessive disorders manifest in males (who have one copy of the X chromosome and are thus hemizygotes), but generally not in female heterozygotes who have one mutant and one normal allele.
 
Gene (location): L1CAM (Xq28)
 
Monarch Initiative: MONDO:0010559
OMIM®: 303350
Orphanet: ORPHA2466

Disease characteristics

Excerpted from the GeneReview: L1 Syndrome
L1 syndrome involves a phenotypic spectrum ranging from severe to mild and includes three clinical phenotypes: X-linked hydrocephalus with stenosis of the aqueduct of Sylvius (HSAS). MASA (mental retardation [intellectual disability], aphasia [delayed speech], spastic paraplegia [shuffling gait], adducted thumbs) syndrome including X-linked complicated hereditary spastic paraplegia type 1. X-linked complicated corpus callosum agenesis. Males with HSAS are born with severe hydrocephalus, adducted thumbs, and spasticity; intellectual disability is severe. In less severely affected males, hydrocephalus may be subclinically present and documented only because of developmental delay; intellectual disability ranges from mild (IQ: 50-70) to moderate (IQ: 30-50). It is important to note that all phenotypes can be observed in affected individuals within the same family. [from GeneReviews]
Authors:
Connie Stumpel  |  Yvonne J Vos   view full author information

Additional descriptions

From OMIM
The hereditary spastic paraplegias (SPG) are a group of clinically and genetically diverse disorders characterized by progressive, usually severe, lower extremity spasticity; see reviews of Fink et al. (1996) and Fink (1997). Some forms of SPG are considered 'uncomplicated,' i.e., progressive spasticity occurs in isolation; others are considered 'complicated,' i.e., progressive spasticity occurs with other neurologic features. X-linked, autosomal dominant (see 182600), and autosomal recessive (see 270800) forms of SPG have been described. Spastic paraplegia-1 is usually called MASA syndrome, the designation originally suggested by Bianchine and Lewis (1974), because the main clinical features are summarized by the acronym MASA (mental retardation, aphasia, shuffling gait, and adducted thumbs). The shuffling gait is probably caused by spasticity of the lower limbs, and all affected males have been reported to have increased reflexes. The adducted thumbs are thought to be caused by hypoplastic or absent extensor pollicis longus or brevis muscles. In affected males, the onset of speech is delayed (Winter et al., 1989). See 314100 for isolated X-linked congenital clasped thumb and 201550 for an autosomal adducted thumbs syndrome. Genetic Heterogeneity of X-linked Spastic Paraplegia Other forms of X-linked spastic paraplegia include SPG2 (312920), caused by mutation in the myelin proteolipid protein gene (PLP1; 300401); SPG16 (300266), mapped to Xq11.2-q23; and SPG34 (300750), mapped to Xq24-q25.  http://www.omim.org/entry/303350
From MedlinePlus Genetics
The life expectancy of individuals with L1 syndrome varies depending on the severity of the signs and symptoms. Severely affected individuals may survive only a short time after birth, while those with mild features live into adulthood.

X-linked complicated corpus callosum agenesis is defined by underdevelopment (hypoplasia) or absence (agenesis) of the tissue that connects the left and right halves of the brain (the corpus callosum). People with this condition can have spastic paraplegia and mild to moderate intellectual disability.

The conditions that make up L1 syndrome were once thought to be distinct disorders, but since they were found to share a genetic cause, they are now considered to be part of the same syndrome. Family members with L1 syndrome caused by the same mutation may have different forms of the condition.

Spastic paraplegia type 1 is characterized by progressive muscle stiffness (spasticity) and the development of paralysis of the limbs (paraplegia). Affected individuals also have mild to moderate intellectual disability. People with spastic paraplegia type 1 do not usually have major abnormalities in structures of the brain.

MASA syndrome is also named for the characteristic features of the condition, which are intellectual disability (mental retardation) that can range from mild to moderate, delayed speech (aphasia), spasticity, and adducted thumbs. Individuals with MASA syndrome may have mild enlargement of the ventricles.

HSAS is an acronym for the characteristic features of the condition: a buildup of fluid in the brain (hydrocephalus) that is often present from before birth, muscle stiffness (spasticity), thumbs that are permanently bent toward the palms (adducted thumbs), and narrowing (stenosis) of a passageway in the brain called the aqueduct of Sylvius. In individuals with HSAS, stenosis of the aqueduct of Sylvius causes hydrocephalus by impeding the flow of cerebrospinal fluid (CSF) out of fluid-filled cavities called ventricles. Individuals with HSAS often have severe intellectual disability and may have seizures.

L1 syndrome describes a group of conditions that primarily affect the nervous system and occur almost exclusively in males. These conditions vary in severity and include, from most severe to least, X-linked hydrocephalus with stenosis of the aqueduct of Sylvius (HSAS), MASA syndrome, spastic paraplegia type 1, and X-linked complicated corpus callosum agenesis.  https://medlineplus.gov/genetics/condition/l1-syndrome

Clinical features

From HPO
Clubfoot
MedGen UID:
3130
Concept ID:
C0009081
Congenital Abnormality
Clubfoot is a congenital limb deformity defined as fixation of the foot in cavus, adductus, varus, and equinus (i.e., inclined inwards, axially rotated outwards, and pointing downwards) with concomitant soft tissue abnormalities (Cardy et al., 2007). Clubfoot may occur in isolation or as part of a syndrome (e.g., diastrophic dysplasia, 222600). Clubfoot has been reported with deficiency of long bones and mirror-image polydactyly (Gurnett et al., 2008; Klopocki et al., 2012).
Thumbs, congenital Clasped
MedGen UID:
98140
Concept ID:
C0431886
Congenital Abnormality
In the resting position, the tip of the thumb is on, or near, the palm, close to the base of the fourth or fifth finger.
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).
Short stature
MedGen UID:
87607
Concept ID:
C0349588
Finding
A height below that which is expected according to age and gender norms. Although there is no universally accepted definition of short stature, many refer to "short stature" as height more than 2 standard deviations below the mean for age and gender (or below the 3rd percentile for age and gender dependent norms).
Aphasia
MedGen UID:
8159
Concept ID:
C0003537
Mental or Behavioral Dysfunction
An acquired language impairment of some or all of the abilities to produce or comprehend speech and to read or write.
Hydrocephalus
MedGen UID:
9335
Concept ID:
C0020255
Disease or Syndrome
Hydrocephalus is an active distension of the ventricular system of the brain resulting from inadequate passage of CSF from its point of production within the cerebral ventricles to its point of absorption into the systemic circulation.
Paraplegia
MedGen UID:
45323
Concept ID:
C0030486
Disease or Syndrome
Severe or complete weakness of both lower extremities with sparing of the upper extremities.
Spastic paraplegia
MedGen UID:
20882
Concept ID:
C0037772
Disease or Syndrome
Spasticity and weakness of the leg and hip muscles.
Corpus callosum, agenesis of
MedGen UID:
104498
Concept ID:
C0175754
Congenital Abnormality
The corpus callosum is the largest fiber tract in the central nervous system and the major interhemispheric fiber bundle in the brain. Formation of the corpus callosum begins as early as 6 weeks' gestation, with the first fibers crossing the midline at 11 to 12 weeks' gestation, and completion of the basic shape by age 18 to 20 weeks (Schell-Apacik et al., 2008). Agenesis of the corpus callosum (ACC) is one of the most frequent malformations in brain with a reported incidence ranging between 0.5 and 70 in 10,000 births. ACC is a clinically and genetically heterogeneous condition, which can be observed either as an isolated condition or as a manifestation in the context of a congenital syndrome (see MOLECULAR GENETICS and Dobyns, 1996). Also see mirror movements-1 and/or agenesis of the corpus callosum (MRMV1; 157600). Schell-Apacik et al. (2008) noted that there is confusion in the literature regarding radiologic terminology concerning partial absence of the corpus callosum, where various designations have been used, including hypogenesis, hypoplasia, partial agenesis, or dysgenesis.
Shuffling gait
MedGen UID:
68545
Concept ID:
C0231688
Finding
A type of gait (walking) characterized by by dragging one's feet along or without lifting the feet fully from the ground.
Lower limb spasticity
MedGen UID:
220865
Concept ID:
C1271100
Finding
Spasticity (velocity-dependent increase in tonic stretch reflexes with increased muscle tone and hyperexcitable tendon reflexes) in the muscles of the lower limbs, hips, and pelvis
Ventriculomegaly
MedGen UID:
480553
Concept ID:
C3278923
Finding
An increase in size of the ventricular system of the brain.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Kyphosis
MedGen UID:
44042
Concept ID:
C0022821
Anatomical Abnormality
Exaggerated anterior convexity of the thoracic vertebral column.
Hyperlordosis
MedGen UID:
9805
Concept ID:
C0024003
Finding
Abnormally increased curvature (anterior concavity) of the lumbar or cervical spine.
Macrocephaly
MedGen UID:
745757
Concept ID:
C2243051
Finding
Occipitofrontal (head) circumference greater than 97th centile compared to appropriate, age matched, sex-matched normal standards. Alternatively, a apparently increased size of the cranium.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Strabismus
MedGen UID:
21337
Concept ID:
C0038379
Disease or Syndrome
A misalignment of the eyes so that the visual axes deviate from bifoveal fixation. The classification of strabismus may be based on a number of features including the relative position of the eyes, whether the deviation is latent or manifest, intermittent or constant, concomitant or otherwise and according to the age of onset and the relevance of any associated refractive error.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
Follow this link to review classifications for MASA syndrome in Orphanet.

Professional guidelines

PubMed

Fransen E, Van Camp G, D'Hooge R, Vits L, Willems PJ
J Med Genet 1998 May;35(5):399-404. doi: 10.1136/jmg.35.5.399. PMID: 9610803Free PMC Article
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Recent clinical studies

Etiology

Chidsey BA, Baldwin EE, Toydemir R, Ahles L, Hanson H, Stevenson DA
Am J Med Genet A 2014 Jun;164A(6):1555-8. Epub 2014 Mar 25 doi: 10.1002/ajmg.a.36474. PMID: 24668863
Liebau MC, Gal A, Superti-Furga A, Omran H, Pohl M
Pediatr Nephrol 2007 Jul;22(7):1058-61. Epub 2007 Feb 10 doi: 10.1007/s00467-006-0424-8. PMID: 17294222
Weller S, Gärtner J
Hum Mutat 2001;18(1):1-12. doi: 10.1002/humu.1144. PMID: 11438988
Uyemura K, Asou H, Yazaki T, Takeda Y
Essays Biochem 1996;31:37-48. PMID: 9078456
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Nat Genet 1994 Jul;7(3):402-7. doi: 10.1038/ng0794-402. PMID: 7920659

Diagnosis

Bousquet I, Bozon M, Castellani V, Touraine R, Piton A, Gérard B, Guibaud L, Sanlaville D, Edery P, Saugier-Veber P, Putoux A
Neurogenetics 2021 Mar;22(1):43-51. Epub 2021 Jan 7 doi: 10.1007/s10048-020-00629-y. PMID: 33415589
Weller S, Gärtner J
Hum Mutat 2001;18(1):1-12. doi: 10.1002/humu.1144. PMID: 11438988
Takahashi S, Makita Y, Okamoto N, Miyamoto A, Oki J
Brain Dev 1997 Dec;19(8):559-62. doi: 10.1016/s0387-7604(97)00079-x. PMID: 9440802
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Fransen E, Lemmon V, Van Camp G, Vits L, Coucke P, Willems PJ
Eur J Hum Genet 1995;3(5):273-84. doi: 10.1159/000472311. PMID: 8556302

Prognosis

Liebau MC, Gal A, Superti-Furga A, Omran H, Pohl M
Pediatr Nephrol 2007 Jul;22(7):1058-61. Epub 2007 Feb 10 doi: 10.1007/s00467-006-0424-8. PMID: 17294222
De Angelis E, Watkins A, Schäfer M, Brümmendorf T, Kenwrick S
Hum Mol Genet 2002 Jan 1;11(1):1-12. doi: 10.1093/hmg/11.1.1. PMID: 11772994
Winter RM, Davies KE, Bell MV, Huson SM, Patterson MN
Hum Genet 1989 Jul;82(4):367-70. doi: 10.1007/BF00273999. PMID: 2737668

Clinical prediction guides

Chidsey BA, Baldwin EE, Toydemir R, Ahles L, Hanson H, Stevenson DA
Am J Med Genet A 2014 Jun;164A(6):1555-8. Epub 2014 Mar 25 doi: 10.1002/ajmg.a.36474. PMID: 24668863
Liebau MC, Gal A, Superti-Furga A, Omran H, Pohl M
Pediatr Nephrol 2007 Jul;22(7):1058-61. Epub 2007 Feb 10 doi: 10.1007/s00467-006-0424-8. PMID: 17294222
De Angelis E, Watkins A, Schäfer M, Brümmendorf T, Kenwrick S
Hum Mol Genet 2002 Jan 1;11(1):1-12. doi: 10.1093/hmg/11.1.1. PMID: 11772994
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J Med Genet 1995 Jul;32(7):549-52. doi: 10.1136/jmg.32.7.549. PMID: 7562969Free PMC Article

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