Pyruvate dehydrogenase E1-alpha deficiency

General Information (adopted from Orphanet):

Synonyms, Signs: PDHAD
pyruvate decarboxylase deficiency
Ataxia, intermittent, with abnormal pyruvate metabolism
Pyruvate dehydrogenase complex deficiency
PDH deficiency
Pyruvate dehydrogenase complex E1 component subunit alpha deficiency
Ataxia with lactic acidosis I lactic acidemia, thiamine-responsive, included
Ataxia, intermittent, with pyruvate dehydrogenase deficiency
Number of Symptoms 73
OrphanetNr: 79243
OMIM Id: 312170
ICD-10: E74.4
UMLs:
MeSH:
MedDRA:
Snomed:

Prevalence, inheritance and age of onset:

Prevalence: No data available.
Inheritance: X-linked
7887409; 10679936 [IBIS]
Age of onset: Neonatal
Infancy
14635113; 7887409 [IBIS]

Disease classification (adopted from Orphanet):

Parent Diseases: Pyruvate dehydrogenase deficiency
 -Rare developmental defect during embryogenesis
 -Rare genetic disease
 -Rare neurologic disease

Comment:

Defects in the pyruvate dehydrogenase (PDH) complex are an important cause of primary lactic acidosis, a frequent manifestation of metabolic disease in children. Clinical symptoms can vary considerably in patients with PDH complex deficiencies, and almost equal numbers of affected males and females have been identified, suggesting an autosomal recessive mode of inheritance of the disease. However, the great majority of PDH complex deficiencies result from mutations in the X-linked pyruvate dehydrogenase (E1) alpha subunit gene (PDHA1). The major factors that contribute to the clinical variation in E1alpha deficiency and its resemblance to a recessive disease are developmental lethality in some males with severe mutations and the pattern of X-inactivation in females (PMID:10679936). Following Chun et al. (1995) PDH E1alpha deficiency could be classified as both an X-linked dominant and X-linked lethal disease, depending on the mutation (PMID:7887409). Other papers assume that the mode of inheritance of PDH E1alpha deficiency is not simply X-linked recessive or dominant but something in between the two. Factors that contribute to its resemblance to a recessive disease are developmental lethality in some males with severe mutations and the pattern of X-inactivation in females. It is not surprising that the majority of mutations in the E1a gene occur de novo (PMID:10679936).

Symptom Information: Sort by abundance 

1
 (HPO:0008872) Feeding difficulties in infancy 14635113 IBIS 153 / 7739
2
 (HPO:0000316) Hypertelorism 9686362 IBIS 644 / 7739
3
 (HPO:0000496) Abnormality of eye movement 9686362 IBIS 79 / 7739
4
 (HPO:0000602) Ophthalmoplegia 23430811 IBIS 56 / 7739
5
 (HPO:0000605) Supranuclear gaze palsy 9686362 IBIS 16 / 7739
6
 (HPO:0000508) Ptosis 9686362 IBIS 459 / 7739
7
 (HPO:0002093) Respiratory insufficiency 7887409 IBIS 410 / 7739
8
 (HPO:0004925) Chronic lactic acidosis 10679936 IBIS 3 / 7739
9
 (HPO:0002151) Increased serum lactate 14635113 IBIS 92 / 7739
10
 (HPO:0003128) Lactic acidosis 14635113 IBIS 116 / 7739
11
 (HPO:0003648) Lacticaciduria 9686362 IBIS 6 / 7739
12
 (HPO:0004900) Severe lactic acidosis 14635113 IBIS 5 / 7739
13
 (HPO:0001942) Metabolic acidosis 14635113 IBIS 81 / 7739
14
 (HPO:0003542) Increased serum pyruvate 16412675 IBIS 18 / 7739
15
 (HPO:0003348) Hyperalaninemia 9686362 IBIS 19 / 7739
16
 (HPO:0002119) Ventriculomegaly 8032855 IBIS 253 / 7739
17
 (HPO:0002928) Decreased activity of the pyruvate dehydrogenase complex 16412675 IBIS 10 / 7739
18
 (HPO:0001252) Muscular hypotonia 7887409 IBIS 990 / 7739
19
 (HPO:0001290) Generalized hypotonia 9686362 IBIS 51 / 7739
20
 (HPO:0008947) Infantile muscular hypotonia 7887409 IBIS 482 / 7739
21
 (HPO:0010547) Muscle flaccidity 14635113 IBIS 466 / 7739
22
 (HPO:0003546) Exercise intolerance 10679936 IBIS 62 / 7739
23
 (HPO:0001324) Muscle weakness 9686362 IBIS 859 / 7739
24
 (HPO:0007340) Lower limb muscle weakness 23430811 IBIS 61 / 7739
25
 (HPO:0003484) Upper limb muscle weakness 23430811 IBIS 19 / 7739
26
 (HPO:0003323) Progressive muscle weakness 23430811 IBIS 17 / 7739
27
 (HPO:0002490) Increased CSF lactate 14635113 IBIS 28 / 7739
28
 (HPO:0003431) Decreased motor nerve conduction velocity 23430811 IBIS 51 / 7739
29
 (HPO:0001298) Encephalopathy 9686362 IBIS 72 / 7739
30
 (HPO:0003477) Peripheral axonal neuropathy 10679936 IBIS 62 / 7739
31
 (HPO:0001251) Ataxia 7887409 IBIS 413 / 7739
32
 (HPO:0002131) Episodic ataxia 7887409 IBIS 16 / 7739
33
 (HPO:0002073) Progressive cerebellar ataxia 7887409 IBIS 27 / 7739
34
 (HPO:0002510) Spastic tetraplegia 10679936 IBIS 54 / 7739
35
 (HPO:0002445) Tetraplegia 10679936 IBIS 26 / 7739
36
 (HPO:0001332) Dystonia 10679936 IBIS 197 / 7739
37
 (HPO:0001263) Global developmental delay 9686362 IBIS 853 / 7739
38
 (HPO:0001249) Intellectual disability 7887409 IBIS 1089 / 7739
39
 (HPO:0010864) Intellectual disability, severe 9686362 IBIS 120 / 7739
40
 (HPO:0001270) Motor delay 23430811 IBIS 322 / 7739
41
 (HPO:0001254) Lethargy 14635113 IBIS 104 / 7739
42
 (HPO:0002015) Dysphagia 9686362 IBIS 301 / 7739
43
 (HPO:0010851) EEG with burst suppression 14635113 IBIS 2 / 7739
44
 (HPO:0001284) Areflexia 9686362 IBIS 198 / 7739
45
 (HPO:0001265) Hyporeflexia 9686362 IBIS 208 / 7739
46
 (HPO:0001250) Seizures 10679936 IBIS 1245 / 7739
47
 (HPO:0000308) Microretrognathia 9686362 IBIS 78 / 7739
48
 (HPO:0002007) Frontal bossing 9141261 IBIS 366 / 7739
49
 (HPO:0000252) Microcephaly 10679936 IBIS 832 / 7739
50
 (HPO:0001274) Agenesis of corpus callosum 10679936 IBIS 142 / 7739
51
 (HPO:0002079) Hypoplasia of the corpus callosum 9686362 IBIS 161 / 7739
52
 (HPO:0001537) Umbilical hernia 9141261 IBIS 206 / 7739
53
 (HPO:0000023) Inguinal hernia 9141261 IBIS 181 / 7739
54
 (HPO:0001999) Abnormal facial shape 9686362 IBIS 169 / 7739
55
 (HPO:0000582) Upslanted palpebral fissure 9141261 IBIS 185 / 7739
56
 (HPO:0000343) Long philtrum 9686362 IBIS 262 / 7739
57
 (HPO:0000463) Anteverted nares 9141261 IBIS 305 / 7739
58
 (HPO:0000707) Abnormality of the nervous system 14635113 IBIS 61 / 7739
59
 (HPO:0000369) Low-set ears 9686362 IBIS 372 / 7739
60
 (HPO:0005949) Apneic episodes in infancy 8024267 IBIS 5 / 7739
61
 (HPO:0012751) Abnormal basal ganglia MRI signal intensity 14635113 IBIS 4 / 7739
62
 (HPO:0012696) Abnormal thalamic MRI signal intensity 14635113 IBIS 2 / 7739
63
 (HPO:0002134) Abnormality of the basal ganglia 7887409 IBIS 13 / 7739
64
 (HPO:0002059) Cerebral atrophy 9686362 IBIS 171 / 7739
65
 (HPO:0002120) Cerebral cortical atrophy 10679936 IBIS 187 / 7739
66
 (HPO:0007266) Cerebral dysmyelination 9686362 IBIS 13 / 7739
67
 (HPO:0003819) Death in childhood 7887409 IBIS 42 / 7739
68
 (HPO:0001522) Death in infancy 7887409 IBIS 275 / 7739
69
 (HPO:0010576) Intracranial cystic lesion 8032855 IBIS 2 / 7739
70
 (HPO:0003811) Neonatal death 14635113 IBIS 44 / 7739
71
 (MedDRA:10051004) Floppy infant 14635113 IBIS 5 / 7739
72
 (MedDRA:10043089) Tachypnoea 9686362 IBIS 1 / 7739
73
 (OMIM) Episodic ptosis 9686362 IBIS 1 / 7739

Associated genes:

PDHA1;

ClinVar (via SNiPA)

Gene symbol Variation Clinical significance Reference

Additional Information:

Description: (OMIM) Genetic defects in the pyruvate dehydrogenase complex are one of the most common causes of primary lactic acidosis in children. Most cases are caused by mutation in the E1-alpha subunit gene on the X chromosome. X-linked PDH deficiency ...
Diagnosis OMIM Brown et al. (1994) reviewed all aspects of PDH deficiency, including prenatal diagnosis and treatment. They noted that the biochemical abnormalities may be minimal and easily overlooked, especially when the patient has extensive structural defects in the brain. ...
Clinical Description OMIM In general, there are 2 major presentations of PDH deficiency, metabolic and neurologic, which occur at equal frequency. The metabolic form presents as severe lactic acidosis in the newborn period, usually leading to death. Patients with the neurologic ...
Molecular genetics OMIM In a male patient with lactic acidosis and decreased pyruvate dehydrogenase E1 activity, Endo et al. (1989) identified a 4-bp deletion in the PDHA1 cDNA (300502.0001). In a female patient with PDH deficiency and decreased levels of the ...