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Amish lethal microcephaly(MCPHA)

MedGen UID:
375938
Concept ID:
C1846648
Disease or Syndrome
Synonyms: MCPHA; Microcephaly, Amish type; THIAMINE METABOLISM DYSFUNCTION SYNDROME 3 (MICROCEPHALY TYPE)
SNOMED CT: Amish microcephaly (702437000); Amish lethal microcephaly (702437000)
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): SLC25A19 (17q25.1)
 
Monarch Initiative: MONDO:0011790
OMIM®: 607196
Orphanet: ORPHA99742

Disease characteristics

SLC25A19-related thiamine metabolism dysfunction (SLC25A19 deficiency) is characterized by two phenotypes: Amish lethal microcephaly and thiamine metabolism dysfunction syndrome 4 (THMD-4). Amish lethal microcephaly is characterized by severe congenital microcephaly, developmental delay, seizures, 2-oxoglutaric aciduria, and often premature death. THMD-4 is characterized by febrile illness-associated episodic encephalopathy, progressive polyneuropathy, and bilateral striatal necrosis. [from GeneReviews]
Authors:
Brahim Tabarki  |  Farah Thabet  |  Majid Alfadhel   view full author information

Additional descriptions

From OMIM
Amish-type microcephaly (MCPHA) is a severe autosomal recessive metabolic disorder characterized by severe microcephaly apparent at birth, profoundly delayed psychomotor development, brain malformations, and episodic encephalopathy associated with lactic acidosis and alpha-ketoglutaric aciduria (summary by Kelley et al., 2002). For a discussion of genetic heterogeneity of disorders due to thiamine metabolism dysfunction, see THMD1 (249270).  http://www.omim.org/entry/607196
From MedlinePlus Genetics
Amish lethal microcephaly is a disorder in which infants are born with an usually small head (microcephaly) and underdeveloped brain.

Infants with Amish lethal microcephaly have a sloping forehead and an extremely small head size. They may also have an unusually small lower jaw and chin (micrognathia) and an enlarged liver (hepatomegaly).

Affected infants may have seizures and difficulty maintaining their body temperature. Often they become very irritable starting in the second or third month of life. A compound called alpha-ketoglutaric acid can be detected in their urine (alpha-ketoglutaric aciduria), and during episodes of viral illness they tend to develop elevated levels of acid in the blood and tissues (metabolic acidosis). Infants with this disorder typically feed adequately but do not develop skills such as purposeful movement or the ability to track faces and sounds. Affected infants live only about six months.  https://medlineplus.gov/genetics/condition/amish-lethal-microcephaly

Clinical features

From HPO
Limb hypertonia
MedGen UID:
333083
Concept ID:
C1838391
Finding
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size of the liver.
Poor suck
MedGen UID:
324693
Concept ID:
C1837142
Finding
An inadequate sucking reflex, resulting in the difficult of newborns to be breast-fed.
Myoclonus
MedGen UID:
10234
Concept ID:
C0027066
Finding
Very brief, involuntary random muscular contractions occurring at rest, in response to sensory stimuli, or accompanying voluntary movements.
Cerebellar hypoplasia
MedGen UID:
120578
Concept ID:
C0266470
Congenital Abnormality
Cerebellar hypoplasia is a descriptive term implying a cerebellum with a reduced volume, but a normal shape and is stable over time.
Partial agenesis of the corpus callosum
MedGen UID:
98127
Concept ID:
C0431368
Congenital Abnormality
A partial failure of the development of the corpus callosum.
Cerebellar vermis hypoplasia
MedGen UID:
333548
Concept ID:
C1840379
Finding
Underdevelopment of the vermis of cerebellum.
Irritability
MedGen UID:
397841
Concept ID:
C2700617
Mental Process
A proneness to anger, i.e., a tendency to become easily bothered or annoyed.
Micrognathia
MedGen UID:
44428
Concept ID:
C0025990
Congenital Abnormality
Developmental hypoplasia of the mandible.
Flexion contracture
MedGen UID:
83069
Concept ID:
C0333068
Anatomical Abnormality
A flexion contracture is a bent (flexed) joint that cannot be straightened actively or passively. It is thus a chronic loss of joint motion due to structural changes in muscle, tendons, ligaments, or skin that prevents normal movement of joints.
Axial hypotonia
MedGen UID:
342959
Concept ID:
C1853743
Finding
Muscular hypotonia (abnormally low muscle tone) affecting the musculature of the trunk.
Small anterior fontanelle
MedGen UID:
347886
Concept ID:
C1859455
Finding
Abnormally decreased size of the anterior fontanelle with respect to age-dependent norms.
Primary microcephaly
MedGen UID:
383046
Concept ID:
C2677180
Finding
Head circumference below 2 standard deviations below the mean for age and gender at birth.
Lactic acidosis
MedGen UID:
1717
Concept ID:
C0001125
Disease or Syndrome
An abnormal buildup of lactic acid in the body, leading to acidification of the blood and other bodily fluids.
Sloping forehead
MedGen UID:
346640
Concept ID:
C1857679
Finding
Inclination of the anterior surface of the forehead from the vertical more than two standard deviations above the mean (objective); or apparently excessive posterior sloping of the forehead in a lateral view.
Optic atrophy
MedGen UID:
18180
Concept ID:
C0029124
Disease or Syndrome
Atrophy of the optic nerve. Optic atrophy results from the death of the retinal ganglion cell axons that comprise the optic nerve and manifesting as a pale optic nerve on fundoscopy.
Foveal hypoplasia
MedGen UID:
393047
Concept ID:
C2673946
Finding
Underdevelopment of the fovea centralis.
Cerebral visual impairment
MedGen UID:
890568
Concept ID:
C4048268
Pathologic Function
A form of loss of vision caused by damage to the visual cortex rather than a defect in the eye.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVAmish lethal microcephaly
Follow this link to review classifications for Amish lethal microcephaly in Orphanet.

Recent clinical studies

Therapy

Brown G
J Inherit Metab Dis 2014 Jul;37(4):577-85. Epub 2014 May 1 doi: 10.1007/s10545-014-9712-9. PMID: 24789339

Prognosis

Porta F, Siri B, Chiesa N, Ricci F, Nika L, Sciortino P, Spada M
J Pediatr Endocrinol Metab 2021 Feb 23;34(2):261-266. Epub 2020 Nov 19 doi: 10.1515/jpem-2020-0139. PMID: 33544541

Clinical prediction guides

Porta F, Siri B, Chiesa N, Ricci F, Nika L, Sciortino P, Spada M
J Pediatr Endocrinol Metab 2021 Feb 23;34(2):261-266. Epub 2020 Nov 19 doi: 10.1515/jpem-2020-0139. PMID: 33544541

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