Alpers syndrome

General Information (adopted from Orphanet):

Synonyms, Signs: MTDPS4A
PNDC
Progressive neuronal degeneration of childhood with liver disease
Alpers-Huttenlocher syndrome
Alpers progressive infantile poliodystrophy
Neuronal degeneration of childhood with liver disease, progressive
Alpers progressive sclerosing poliodystrophy
Alpers diffuse degeneration of cerebral gray matter with hepatic cirrhosis
Number of Symptoms 84
OrphanetNr: 726
OMIM Id: 203700
ICD-10: G31.8
UMLs: C0205710
MeSH: D002549
MedDRA: 10062943
Snomed: 20415001

Prevalence, inheritance and age of onset:

Prevalence: 0.7 [Orphanet]
Inheritance: Monogenic
Autosomal recessive
23419467 [IBIS]
Age of onset: Infancy
Childhood
Adolescent
Adult
23419467; 16957900 [IBIS]

Disease classification (adopted from Orphanet):

Parent Diseases: Genetic neurodegenerative disease
 -Rare genetic disease
Mitochondrial DNA depletion syndrome
 -Rare developmental defect during embryogenesis
 -Rare eye disease
 -Rare gastroenterologic disease
 -Rare genetic disease
 -Rare neurologic disease
Mitochondrial disease with epilepsy
 -Rare neurologic disease
Mitochondrial disease with peripheral neuropathy
 -Rare genetic disease
 -Rare neurologic disease
Neurometabolic disease
 -Rare genetic disease
 -Rare neurologic disease
Rare neurodegenerative disease
 -Rare neurologic disease

Comment:

Alpers-Huttenlocher syndrome is an uncommon mitochondrial disease most often associated with mutations in the mitochondrial DNA polymerase gamma (= POLG = MTDPS4A). The hallmark clinical features of Alpers-Huttenlocher syndrome are intractable seizures, developmental regression and liver dysfunction. This triad of clinical hepatocerebral symptoms and seizures, when combined with 2 of 11 other findings, constitute the clinical diagnosis of Alpers-Huttenlocher Syndrome. Both the tempo of disease progression and range of organ involvement vary from patient to patient, and are only partly explained by pathogenic effects of genetic mutations. Alpers-Huttenlocher syndrome is an autosomal recessive disorder. Homozygote dominant polymerase gamma mutations or even a dominant polymerase gamma mutation with a recessive mutation have not been described, suggesting that these possible mutation combinations are likely embryonic lethal. The most common age of onset is between 2–4 years, with a range of 3 months to 8 years. The age of Alpers-Huttenlocher syndrome onset is bimodal with a second peak onset between 17–24 years, with a range of 10 – 27 years. Infants and children with Alpers-Huttenlocher syndrome are healthy until disease onset, although some have identified non-specific developmental delays. There is no precise phenotype to genotype correlation, although there are suggestions that location of mutations within specific regions of polymerase gamma may play a role in the phenotypic expression of the disorder. Age of onset is influenced, in part, by specific mutations within the polymerase gamma gene, other genes, and environmental factors such as intercurrent viral infections and certain medications like valproic acid (PMID:23419467). Multiple oxidative phosphorylation deficiencies in severe childhood multi-system disorders due to polymerase gamma (POLG1) mutations not always show the clinical picture of Alpers syndrome. Contrary to reports in literature, the classical picture of Alpers syndrome was obvious in only three of eight patients described in de Vries et al. (2007) (with the mutations R227W/A467T, 679C>T/1399G>A; G848S/A467T, 2542G>A/1399G>A; and A957P/A467T, 2869G>C/1399G>A). Other patients mentioned in this paper developed liver failure in an advanced stage of the disease (multiple organ failure) and after administration of sodium valproate.(PMID:16957900). Hakonen et al. (2007) describes that the POLG mutations W748S, A467T, and G848S in the catalytic subunit of POLG underlie various severe central nervous system phenotypes, ranging from infantile Alpers syndrome to mitochondrial recessive ataxia syndrome (MIRAS) with juvenile or adult onset. In the case of Alpers syndrome, most patients with a defined genetic background carry either the W748S or the A467T mutation in combination with another POLG mutation, most commonly G848S (PMID:17426723).

Symptom Information: Sort by abundance 

1
 (HPO:0002013) Vomiting 23419467 IBIS 191 / 7739
2
 (HPO:0000590) Progressive external ophthalmoplegia 23419467 IBIS 23 / 7739
3
 (HPO:0000649) Abnormality of visual evoked potentials 23419467 IBIS 34 / 7739
4
 (HPO:0000505) Visual impairment 15328560 IBIS 297 / 7739
5
 (HPO:0000618) Blindness 23419467 IBIS 124 / 7739
6
 (HPO:0100704) Cortical visual impairment 23419467 IBIS 28 / 7739
7
 (HPO:0000572) Visual loss 23419467 IBIS 272 / 7739
8
 (HPO:0002151) Increased serum lactate 23419467 IBIS 92 / 7739
9
 (HPO:0001508) Failure to thrive 23419467 IBIS 454 / 7739
10
 (HPO:0003355) Aminoaciduria 16957900 IBIS 65 / 7739
11
 (HPO:0003535) 3-Methylglutaconic aciduria 23419467 IBIS 10 / 7739
12
 (HPO:0003219) Ethylmalonic aciduria 16957900 IBIS 5 / 7739
13
 (HPO:0001638) Cardiomyopathy Occasional [IBIS] 10% 23419467 IBIS 192 / 7739
14
 (HPO:0002119) Ventriculomegaly 23419467 IBIS 253 / 7739
15
 (HPO:0001635) Congestive heart failure Occasional [IBIS] 23419467 IBIS 232 / 7739
16
 (HPO:0008972) Decreased activity of mitochondrial respiratory chain 23419467 IBIS 34 / 7739
17
 (HPO:0011923) Decreased activity of mitochondrial complex I 23419467 IBIS 35 / 7739
18
 (HPO:0011924) Decreased activity of mitochondrial complex III 23419467 IBIS 22 / 7739
19
 (HPO:0008347) Decreased activity of mitochondrial complex IV 23419467 IBIS 31 / 7739
20
 (HPO:0001414) Microvesicular hepatic steatosis 23419467 IBIS 9 / 7739
21
 (HPO:0003198) Myopathy 23419467 IBIS 151 / 7739
22
 (HPO:0001252) Muscular hypotonia Frequent [Orphanet] 23419467 IBIS 990 / 7739
23
 (HPO:0008947) Infantile muscular hypotonia 16957900 IBIS 482 / 7739
24
 (HPO:0002305) Athetosis 23419467 IBIS 31 / 7739
25
 (HPO:0002072) Chorea 23419467 IBIS 53 / 7739
26
 (HPO:0001336) Myoclonus 23419467 IBIS 115 / 7739
27
 (HPO:0002490) Increased CSF lactate 23419467 IBIS 28 / 7739
28
 (HPO:0002922) Increased CSF protein 22000311 IBIS 27 / 7739
29
 (HPO:0001251) Ataxia 23419467 IBIS 413 / 7739
30
 (HPO:0002066) Gait ataxia Frequent [Orphanet] 15122711 IBIS 327 / 7739
31
 (HPO:0001276) Hypertonia Frequent [Orphanet] 15122711 IBIS 317 / 7739
32
 (HPO:0004374) Hemiplegia/hemiparesis Frequent [Orphanet] 22000311 IBIS 158 / 7739
33
 (HPO:0000726) Dementia 23419467 IBIS 131 / 7739
34
 (HPO:0002376) Developmental regression Frequent [IBIS] 23419467 IBIS 74 / 7739
35
 (HPO:0001263) Global developmental delay Frequent [IBIS] 23419467 IBIS 853 / 7739
36
 (HPO:0100022) Abnormality of movement Frequent [Orphanet] 23419467 IBIS 129 / 7739
37
 (HPO:0001337) Tremor 22000311 IBIS 200 / 7739
38
 (HPO:0002353) EEG abnormality 23419467 IBIS 188 / 7739
39
 (HPO:0011182) Epileptiform EEG discharges 23419467 IBIS 1 / 7739
40
 (HPO:0001250) Seizures Frequent [IBIS] Frequent [Orphanet] 23419467 IBIS 1245 / 7739
41
 (HPO:0011153) Focal motor seizures Frequent [IBIS] 22000311 IBIS 2 / 7739
42
 (HPO:0002123) Generalized myoclonic seizures Frequent [IBIS] 22000311 IBIS 62 / 7739
43
 (HPO:0002133) Status epilepticus Frequent [IBIS] 22000311 IBIS 59 / 7739
44
 (HPO:0000252) Microcephaly Frequent [Orphanet] 22237560 IBIS 832 / 7739
45
 (HPO:0002579) Gastrointestinal dysmotility 23419467 IBIS 11 / 7739
46
 (HPO:0001408) Bile duct proliferation 23419467 IBIS 22 / 7739
47
 (HPO:0001394) Cirrhosis 23419467 IBIS 102 / 7739
48
 (HPO:0001413) Micronodular cirrhosis 15122711 IBIS 11 / 7739
49
 (HPO:0001410) Decreased liver function Frequent [IBIS] 23419467 IBIS 59 / 7739
50
 (HPO:0001399) Hepatic failure 23419467 IBIS 80 / 7739
51
 (HPO:0006581) Depletion of mitochondrial DNA in liver 23419467 IBIS 3 / 7739
52
 (HPO:0002910) Elevated hepatic transaminases 15122711 IBIS 158 / 7739
53
 (HPO:0002605) Hepatic necrosis 23419467 IBIS 6 / 7739
54
 (HPO:0002240) Hepatomegaly 1861211 IBIS 467 / 7739
55
 (HPO:0000365) Hearing impairment 16957900 IBIS 539 / 7739
56
 (HPO:0009141) Depletion of mitochondrial DNA in muscle tissue 23419467 IBIS 5 / 7739
57
 (HPO:0012705) Abnormal metabolic brain imaging by MRS 23419467 IBIS 1 / 7739
58
 (HPO:0002446) Astrocytosis 23419467 IBIS 7 / 7739
59
 (HPO:0012444) Brain atrophy 23419467 IBIS 24 / 7739
60
 (HPO:0001272) Cerebellar atrophy 23419467 IBIS 197 / 7739
61
 (HPO:0002059) Cerebral atrophy 16957900 IBIS 171 / 7739
62
 (HPO:0006790) Cerebral cortex with spongiform changes 22000311 IBIS 2 / 7739
63
 (HPO:0006964) Cerebral cortical neurodegeneration 23419467 IBIS 1 / 7739
64
 (HPO:0012448) Delayed myelination 16957900 IBIS 51 / 7739
65
 (HPO:0012707) Elevated brain lactate level by MRS 23419467 IBIS 2 / 7739
66
 (HPO:0012847) Epilepsia partialis continua 23419467 IBIS 1 / 7739
67
 (HPO:0002171) Gliosis 23419467 IBIS 48 / 7739
68
 (HPO:0012852) Hepatic bridging fibrosis 23419467 IBIS 1 / 7739
69
 (HPO:0007183) Focal T2 hyperintense basal ganglia lesion 23419467 IBIS 6 / 7739
70
 (HPO:0002529) Neuronal loss in central nervous system 23419467 IBIS 37 / 7739
71
 (HPO:0003678) Rapidly progressive 23419467 IBIS 33 / 7739
72
 (HPO:0012708) Reduced brain N-acetyl aspartate level by MRS 23419467 IBIS 2 / 7739
73
 (MedDRA:10059396) Mitochondrial DNA depletion 23419467 IBIS 5 / 7739
74
 (OMIM) Abnormal bile duct architecture 23419467 IBIS 1 / 7739
75
 (OMIM) Biopsy shows microvesicular steatosis 23419467 IBIS 1 / 7739
76
 (OMIM) Decreased DNA polymerase-gamma (POLG, 174763) activity 23419467 IBIS 1 / 7739
77
 (OMIM) Decreased mitochondrial respiratory chain complex activity 23419467 IBIS 2 / 7739
78
 (OMIM) EEG shows slow frequency high amplitude waves with high frequency polyspikes 23419467 IBIS 1 / 7739
79
 (OMIM) Hepatocyte dropout 23419467 IBIS 1 / 7739
80
 (OMIM) Intractable seizures Frequent [IBIS] 23419467 IBIS 12 / 7739
81
 (OMIM) Mitochondrial proliferation 23419467 IBIS 4 / 7739
82
 (OMIM) Normal electroretinogram 23419467 IBIS 4 / 7739
83
 (OMIM) Oncocytic changes 23419467 IBIS 2 / 7739
84
 (OMIM) Portal inflammation 23419467 IBIS 3 / 7739

Associated genes:

POLG;

ClinVar (via SNiPA)

Gene symbol Variation Clinical significance Reference

Additional Information:

Description: (OMIM) Mitochondrial DNA depletion syndrome-4A, also known as Alpers syndrome, is an autosomal recessive disorder characterized by a clinical triad of psychomotor retardation, intractable epilepsy, and liver failure in infants and young children. Pathologic findings include neuronal loss in ...
Clinical Description OMIM Bernard Alpers (1931) described the neuropathology and clinical features in a 4-month-old girl with a one-month illness characterized by intractable generalized seizures. He termed the disorder 'diffuse progressive degeneration of the gray matter of the cerebrum.' Morse (1949) ...
Genotype-Phenotype Correlations OMIM Nguyen et al. (2005) reported a child with Alpers syndrome who was homozygous for the A467T mutation (174763.0002). Unlike other children with the disorder, he showed late onset at age 8.5 years and death by age 9 years. ...
Molecular genetics OMIM Naviaux and Nguyen (2004) reported 3 patients with Alpers syndrome who were homozygous for a mutation (E873X; 174763.0008) in the POLG gene. They later published a correction (Naviaux and Nguyen, 2005) stating that 2 affected patients from 1 ...