MCPHA
MCID: MCR257
MIFTS: 35

Microcephaly, Amish Type (MCPHA)

Categories: Fetal diseases, Genetic diseases, Liver diseases, Metabolic diseases, Nephrological diseases, Neuronal diseases, Rare diseases

Aliases & Classifications for Microcephaly, Amish Type

MalaCards integrated aliases for Microcephaly, Amish Type:

Name: Microcephaly, Amish Type 57 20 43 72 36 13 39 70
Amish Lethal Microcephaly 57 25 20 43 58 72 29 6
Mcpha 57 25 20 43 72
Amish Microcephaly 25 43
Thiamine Metabolism Dysfunction Syndrome 3 ; Thmd3 57
Thiamine Metabolism Dysfunction Syndrome 3 57
Thmd3 57

Characteristics:

Orphanet epidemiological data:

58
amish lethal microcephaly
Inheritance: Autosomal recessive; Age of onset: Infancy,Neonatal; Age of death: late childhood;

OMIM®:

57 (Updated 05-Apr-2021)
Inheritance:
autosomal recessive

Miscellaneous:
onset at birth
progression of the disorder is precipitated by viral symptoms
death usually within first year of life
incidence of 1 in 480 among old order amish
carrier rate of 1 in 11 among old order amish


HPO:

31
microcephaly, amish type:
Onset and clinical course death in infancy congenital onset
Inheritance autosomal recessive inheritance


Classifications:

Orphanet: 58  
Rare neurological diseases
Inborn errors of metabolism
Developmental anomalies during embryogenesis


External Ids:

OMIM® 57 607196
OMIM Phenotypic Series 57 PS249270
KEGG 36 H00990
MeSH 44 D008831
MESH via Orphanet 45 C538247
ICD10 via Orphanet 33 Q02
UMLS via Orphanet 71 C1846648
Orphanet 58 ORPHA99742
MedGen 41 C1846648
UMLS 70 C1846648

Summaries for Microcephaly, Amish Type

MedlinePlus Genetics : 43 Amish lethal microcephaly is a disorder in which infants are born with a very small head 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.

MalaCards based summary : Microcephaly, Amish Type, also known as amish lethal microcephaly, is related to microcephaly and autosomal recessive disease. An important gene associated with Microcephaly, Amish Type is SLC25A19 (Solute Carrier Family 25 Member 19). Affiliated tissues include brain, cerebellum and pons, and related phenotypes are microcephaly and optic atrophy

GARD : 20 The following summary is from Orphanet, a European reference portal for information on rare diseases and orphan drugs. Orpha Number: 99742 Definition A very rare syndrome characterized by extreme microcephaly and early death, within the first year. Epidemiology It has been described only in the Old Order Amish of Lancaster County Pennsylvania. In this population, birth prevalence is about 1/500. Clinical description Microcephaly is a microcephalia vera (MV), evident at birth or through 22-week fetal ultrasound. Affected children have high urinary levels of alpha-ketoglutaric acid. Etiology All affected infants are homozygous for the same mutation of the SLC25A19 gene on chromosome 17 (17q25.3). Genetic counseling The condition follows an autosomal recessive pattern of inheritance. Prognosis Prognosis is very poor: the average life span of affected infants is between five and six months.

OMIM® : 57 Amish-type microcephaly 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). (607196) (Updated 05-Apr-2021)

KEGG : 36 Microcephaly, Amish type (MCPHA) is a lethal, autosomal resessive condition characterized by severe congenital microcephaly, elevated levels of alpha-ketoglutarate in the urine, and premature death. This disorder has been observed in Old Order Amish families. Patients have a homozygous point mutation in SLC25A19 that results in loss of transport activity.

UniProtKB/Swiss-Prot : 72 Microcephaly, Amish type: A disorder characterized by severe congenital microcephaly and severe 2-ketoglutaric aciduria leading to death within the first year.

GeneReviews: NBK1365

Related Diseases for Microcephaly, Amish Type

Diseases related to Microcephaly, Amish Type via text searches within MalaCards or GeneCards Suite gene sharing:

# Related Disease Score Top Affiliating Genes
1 microcephaly 10.2
2 autosomal recessive disease 10.1
3 metabolic acidosis 10.1
4 lactic acidosis 10.1
5 corpus callosum, partial agenesis of, x-linked 9.9
6 lissencephaly 9.9

Graphical network of the top 20 diseases related to Microcephaly, Amish Type:



Diseases related to Microcephaly, Amish Type

Symptoms & Phenotypes for Microcephaly, Amish Type

Human phenotypes related to Microcephaly, Amish Type:

58 31 (show all 33)
# Description HPO Frequency Orphanet Frequency HPO Source Accession
1 microcephaly 58 31 hallmark (90%) Very frequent (99-80%) HP:0000252
2 optic atrophy 58 31 hallmark (90%) Very frequent (99-80%) HP:0000648
3 micrognathia 58 31 hallmark (90%) Very frequent (99-80%) HP:0000347
4 irritability 58 31 hallmark (90%) Very frequent (99-80%) HP:0000737
5 severe global developmental delay 58 31 hallmark (90%) Very frequent (99-80%) HP:0011344
6 sloping forehead 58 31 hallmark (90%) Very frequent (99-80%) HP:0000340
7 feeding difficulties 58 31 hallmark (90%) Very frequent (99-80%) HP:0011968
8 metabolic acidosis 58 31 hallmark (90%) Very frequent (99-80%) HP:0001942
9 organic aciduria 58 31 hallmark (90%) Very frequent (99-80%) HP:0001992
10 cerebellar vermis hypoplasia 58 31 hallmark (90%) Very frequent (99-80%) HP:0001320
11 agenesis of corpus callosum 58 31 frequent (33%) Frequent (79-30%) HP:0001274
12 osteoporosis 58 31 frequent (33%) Frequent (79-30%) HP:0000939
13 ventriculomegaly 58 31 frequent (33%) Frequent (79-30%) HP:0002119
14 spina bifida 58 31 frequent (33%) Frequent (79-30%) HP:0002414
15 lissencephaly 58 31 frequent (33%) Frequent (79-30%) HP:0001339
16 limb hypertonia 58 31 frequent (33%) Frequent (79-30%) HP:0002509
17 temperature instability 58 31 frequent (33%) Frequent (79-30%) HP:0005968
18 hypotonia 31 frequent (33%) HP:0001252
19 hepatomegaly 58 31 occasional (7.5%) Occasional (29-5%) HP:0002240
20 decreased fetal movement 58 31 occasional (7.5%) Occasional (29-5%) HP:0001558
21 limitation of joint mobility 58 31 occasional (7.5%) Occasional (29-5%) HP:0001376
22 decreased skull ossification 58 31 occasional (7.5%) Occasional (29-5%) HP:0004331
23 cleft soft palate 58 31 occasional (7.5%) Occasional (29-5%) HP:0000185
24 bilateral tonic-clonic seizure 31 occasional (7.5%) HP:0002069
25 muscular hypotonia 58 Frequent (79-30%)
26 flexion contracture 31 HP:0001371
27 death in infancy 58 Very frequent (99-80%)
28 cerebellar hypoplasia 31 HP:0001321
29 partial agenesis of the corpus callosum 31 HP:0001338
30 lactic acidosis 31 HP:0003128
31 generalized tonic-clonic seizures 58 Occasional (29-5%)
32 muscular hypotonia of the trunk 31 HP:0008936
33 progressive microcephaly 31 HP:0000253

Symptoms via clinical synopsis from OMIM®:

57 (Updated 05-Apr-2021)
Head And Neck Face:
micrognathia

Neurologic Central Nervous System:
partial agenesis of the corpus callosum
limb hypertonia
hypoplastic cerebellum
truncal hypotonia
no psychomotor development
more
Laboratory Abnormalities:
increased urinary lactate
increased urinary 2-ketoglutarate (variable)

Abdomen Liver:
hepatomegaly associated with infection

Metabolic Features:
lactic acidosis during infection

Neurologic Behavioral Psychiatric Manifestations:
irritability

Skeletal:
contractures

Head And Neck Head:
microcephaly, extreme

Skeletal Skull:
nearly absent cranial vault
absence of anterior and posterior fontanelles

Clinical features from OMIM®:

607196 (Updated 05-Apr-2021)

Drugs & Therapeutics for Microcephaly, Amish Type

Search Clinical Trials , NIH Clinical Center for Microcephaly, Amish Type

Genetic Tests for Microcephaly, Amish Type

Genetic tests related to Microcephaly, Amish Type:

# Genetic test Affiliating Genes
1 Amish Lethal Microcephaly 29 SLC25A19

Anatomical Context for Microcephaly, Amish Type

MalaCards organs/tissues related to Microcephaly, Amish Type:

40
Brain, Cerebellum, Pons

Publications for Microcephaly, Amish Type

Articles related to Microcephaly, Amish Type:

(show all 14)
# Title Authors PMID Year
1
Mutant deoxynucleotide carrier is associated with congenital microcephaly. 57 25 6
12185364 2002
2
Amish lethal microcephaly: a new metabolic disorder with severe congenital microcephaly and 2-ketoglutaric aciduria. 57 25 61
12376931 2002
3
Amish microcephaly: Long-term survival and biochemical characterization. 57 25
20583149 2010
4
SLC25A19 mutation as a cause of neuropathy and bilateral striatal necrosis. 25 6
19798730 2009
5
Knockout of Slc25a19 causes mitochondrial thiamine pyrophosphate depletion, embryonic lethality, CNS malformations, and anemia. 25 61
17035501 2006
6
ALFY-Controlled DVL3 Autophagy Regulates Wnt Signaling, Determining Human Brain Size. 25
27008544 2016
7
The human mitochondrial deoxynucleotide carrier and its role in the toxicity of nucleoside antivirals. 25
11226231 2001
8
Genomic organization and mapping of the gene (SLC25A19) encoding the human mitochondrial deoxynucleotide carrier (DNC). 25
11474176 2001
9
2-ketoglutarate dehydrogenase deficiency with intermittent 2-ketoglutaric aciduria. 25
10774994 2000
10
SLC25A19 deficiency and bilateral striatal necrosis with polyneuropathy: a new case and review of the literature. 61
33544541 2021
11
Functional analysis of the third identified SLC25A19 mutation causative for the thiamine metabolism dysfunction syndrome 4. 61
31506564 2019
12
Defects of thiamine transport and metabolism. 61
24789339 2014
13
Mitochondrial uptake of thiamin pyrophosphate: physiological and cell biological aspects. 61
24023687 2013
14
Amish Lethal Microcephaly 61
20301539 2003

Variations for Microcephaly, Amish Type

ClinVar genetic disease variations for Microcephaly, Amish Type:

6 (show all 38)
# Gene Name Type Significance ClinVarId dbSNP ID Position
1 SLC25A19 NM_001126121.2(SLC25A19):c.530G>C (p.Gly177Ala) SNV Pathogenic 4269 rs119473030 GRCh37: 17:73274346-73274346
GRCh38: 17:75278265-75278265
2 MIF4GD-DT , SLC25A19 NM_001126121.2(SLC25A19):c.775-1G>C SNV Pathogenic 692005 rs372041843 GRCh37: 17:73269721-73269721
GRCh38: 17:75273640-75273640
3 SLC25A19 NM_001126121.2(SLC25A19):c.470C>T (p.Thr157Met) SNV Likely pathogenic 692004 rs554218525 GRCh37: 17:73274406-73274406
GRCh38: 17:75278325-75278325
4 SLC25A19 NM_001126121.2(SLC25A19):c.246C>T (p.His82=) SNV Uncertain significance 325067 rs535476833 GRCh37: 17:73282427-73282427
GRCh38: 17:75286346-75286346
5 SLC25A19 NM_001126121.2(SLC25A19):c.590G>T (p.Ser197Ile) SNV Uncertain significance 198247 rs769399113 GRCh37: 17:73274286-73274286
GRCh38: 17:75278205-75278205
6 SLC25A19 NM_001126121.2(SLC25A19):c.504C>T (p.Ser168=) SNV Uncertain significance 285906 rs148474667 GRCh37: 17:73274372-73274372
GRCh38: 17:75278291-75278291
7 SLC25A19 NM_001126121.2(SLC25A19):c.135T>A (p.Leu45=) SNV Uncertain significance 197331 rs373190423 GRCh37: 17:73282538-73282538
GRCh38: 17:75286457-75286457
8 MIF4GD-DT , SLC25A19 NM_001126121.2(SLC25A19):c.*292A>G SNV Uncertain significance 889457 GRCh37: 17:73269240-73269240
GRCh38: 17:75273159-75273159
9 SLC25A19 NM_001126121.2(SLC25A19):c.155G>A (p.Arg52His) SNV Uncertain significance 782161 rs138954932 GRCh37: 17:73282518-73282518
GRCh38: 17:75286437-75286437
10 SLC25A19 NM_001126121.2(SLC25A19):c.93G>A (p.Ala31=) SNV Uncertain significance 597165 rs143765189 GRCh37: 17:73282753-73282753
GRCh38: 17:75286672-75286672
11 SLC25A19 NM_001126121.2(SLC25A19):c.-170G>A SNV Uncertain significance 891959 GRCh37: 17:73285476-73285476
GRCh38: 17:75289395-75289395
12 MIF4GD-DT , SLC25A19 NM_001126121.2(SLC25A19):c.*408C>T SNV Uncertain significance 889454 GRCh37: 17:73269124-73269124
GRCh38: 17:75273043-75273043
13 MIF4GD-DT , SLC25A19 NM_001126121.2(SLC25A19):c.*384C>T SNV Uncertain significance 889455 GRCh37: 17:73269148-73269148
GRCh38: 17:75273067-75273067
14 MIF4GD-DT , SLC25A19 NM_001126121.2(SLC25A19):c.930C>A (p.Phe310Leu) SNV Uncertain significance 325065 rs886053391 GRCh37: 17:73269565-73269565
GRCh38: 17:75273484-75273484
15 SLC25A19 NM_001126121.2(SLC25A19):c.20A>G (p.Lys7Arg) SNV Uncertain significance 325068 rs762770947 GRCh37: 17:73282826-73282826
GRCh38: 17:75286745-75286745
16 SLC25A19 NM_001126121.2(SLC25A19):c.324C>G (p.His108Gln) SNV Uncertain significance 325066 rs146573563 GRCh37: 17:73279639-73279639
GRCh38: 17:75283558-75283558
17 SLC25A19 NM_001126121.2(SLC25A19):c.73T>G (p.Ser25Ala) SNV Uncertain significance 436748 rs777474053 GRCh37: 17:73282773-73282773
GRCh38: 17:75286692-75286692
18 MIF4GD-DT , SLC25A19 NM_001126121.2(SLC25A19):c.*113G>C SNV Uncertain significance 325064 rs780528476 GRCh37: 17:73269419-73269419
GRCh38: 17:75273338-75273338
19 SLC25A19 NM_001126121.2(SLC25A19):c.622C>T (p.Pro208Ser) SNV Uncertain significance 96021 rs200276538 GRCh37: 17:73274254-73274254
GRCh38: 17:75278173-75278173
20 SLC25A19 NM_001126121.2(SLC25A19):c.476G>A (p.Arg159His) SNV Uncertain significance 890720 GRCh37: 17:73274400-73274400
GRCh38: 17:75278319-75278319
21 MIF4GD-DT , SLC25A19 NM_001126121.2(SLC25A19):c.779G>A (p.Arg260Gln) SNV Uncertain significance 1029820 GRCh37: 17:73269716-73269716
GRCh38: 17:75273635-75273635
22 MIF4GD-DT , SLC25A19 NM_001126121.2(SLC25A19):c.842T>G (p.Phe281Cys) SNV Uncertain significance 596497 rs138376525 GRCh37: 17:73269653-73269653
GRCh38: 17:75273572-75273572
23 SLC25A19 NM_021734.4(SLC25A19):c.-201T>A SNV Likely benign 325071 rs576181366 GRCh37: 17:73285523-73285523
GRCh38: 17:75289442-75289442
24 MIF4GD-DT , SLC25A19 NM_001126121.2(SLC25A19):c.*301C>T SNV Likely benign 889456 GRCh37: 17:73269231-73269231
GRCh38: 17:75273150-75273150
25 SLC25A19 NM_001126121.2(SLC25A19):c.483C>T (p.Ala161=) SNV Likely benign 198248 rs142281464 GRCh37: 17:73274393-73274393
GRCh38: 17:75278312-75278312
26 SLC25A19 NM_001126121.2(SLC25A19):c.-173_-172AG[2] Microsatellite Likely benign 325070 rs796850773 GRCh37: 17:73285472-73285475
GRCh38: 17:75289391-75289394
27 SLC25A19 NM_001126121.2(SLC25A19):c.288+8G>C SNV Likely benign 506459 rs144563813 GRCh37: 17:73282377-73282377
GRCh38: 17:75286296-75286296
28 SLC25A19 NM_001126121.2(SLC25A19):c.642T>C (p.Asn214=) SNV Likely benign 386288 rs147091827 GRCh37: 17:73274234-73274234
GRCh38: 17:75278153-75278153
29 MIF4GD-DT , SLC25A19 NM_001126121.2(SLC25A19):c.797T>G (p.Met266Arg) SNV Likely benign 281113 rs148372053 GRCh37: 17:73269698-73269698
GRCh38: 17:75273617-75273617
30 MIF4GD-DT , SLC25A19 NM_001126121.2(SLC25A19):c.*96G>C SNV Likely benign 890140 GRCh37: 17:73269436-73269436
GRCh38: 17:75273355-75273355
31 MIF4GD-DT , SLC25A19 NM_001126121.2(SLC25A19):c.*200G>A SNV Benign 325063 rs62622012 GRCh37: 17:73269332-73269332
GRCh38: 17:75273251-75273251
32 MIF4GD-DT , SLC25A19 NM_001126121.2(SLC25A19):c.*164G>A SNV Benign 890139 GRCh37: 17:73269368-73269368
GRCh38: 17:75273287-75273287
33 MIF4GD-DT , SLC25A19 NM_001126121.2(SLC25A19):c.819G>A (p.Leu273=) SNV Benign 130333 rs4789164 GRCh37: 17:73269676-73269676
GRCh38: 17:75273595-75273595
34 MIF4GD-DT , SLC25A19 NM_001126121.2(SLC25A19):c.*437T>G SNV Benign 325061 rs73356384 GRCh37: 17:73269095-73269095
GRCh38: 17:75273014-75273014
35 SLC25A19 NM_001126121.2(SLC25A19):c.-155T>G SNV Benign 325069 rs2291033 GRCh37: 17:73285461-73285461
GRCh38: 17:75289380-75289380
36 MIF4GD-DT , SLC25A19 NM_001126121.2(SLC25A19):c.*2T>C SNV Benign 130327 rs1809352 GRCh37: 17:73269530-73269530
GRCh38: 17:75273449-75273449
37 MIF4GD-DT , SLC25A19 NM_001126121.2(SLC25A19):c.*274C>G SNV Benign 325062 rs7198 GRCh37: 17:73269258-73269258
GRCh38: 17:75273177-75273177
38 SLC25A19 NM_001126121.2(SLC25A19):c.339T>C (p.Tyr113=) SNV Benign 130330 rs7213318 GRCh37: 17:73279624-73279624
GRCh38: 17:75283543-75283543

UniProtKB/Swiss-Prot genetic disease variations for Microcephaly, Amish Type:

72
# Symbol AA change Variation ID SNP ID
1 SLC25A19 p.Gly177Ala VAR_014103 rs119473030

Expression for Microcephaly, Amish Type

Search GEO for disease gene expression data for Microcephaly, Amish Type.

Pathways for Microcephaly, Amish Type

GO Terms for Microcephaly, Amish Type

Sources for Microcephaly, Amish Type

3 CDC
7 CNVD
9 Cosmic
10 dbSNP
11 DGIdb
17 EFO
18 ExPASy
19 FMA
20 GARD
28 GO
29 GTR
30 HMDB
31 HPO
32 ICD10
33 ICD10 via Orphanet
34 ICD9CM
35 IUPHAR
36 KEGG
37 LifeMap
39 LOVD
41 MedGen
44 MeSH
45 MESH via Orphanet
46 MGI
49 NCI
50 NCIt
51 NDF-RT
53 NINDS
54 Novoseek
56 OMIM via Orphanet
57 OMIM® (Updated 05-Apr-2021)
61 PubMed
63 QIAGEN
68 SNOMED-CT via HPO
69 Tocris
70 UMLS
71 UMLS via Orphanet
Content
Loading form....