Congenital lactic acidosis, Saguenay-Lac-St. Jean type

General Information (adopted from Orphanet):

Synonyms, Signs: LSFC
Saguenay-Lac-St. Jean type Leigh syndrome
French-Canadian type cytochrome C oxidase deficiency
Leigh syndrome, Saguenay-Lac-Saint-Jean type
Cytochrome C oxidase deficiency, French Canadian type
French-Canadian type COX deficiency
French-Canadian type Leigh syndrome
COX deficiency, French Canadian type
SLSJ-COX deficiency
Saguenay-Lac-St. Jean cytochrome oxidase deficiency
COX deficiency, Saguenay-Lac-Saint-Jean Type
Number of Symptoms 63
OrphanetNr: 70472
OMIM Id: 220111
ICD-10: G31.8
UMLs:
MeSH:
MedDRA:
Snomed:

Prevalence, inheritance and age of onset:

Prevalence: No data available.
Inheritance: Autosomal recessive
21266382 [IBIS]
Age of onset: Neonatal
Infancy
26510951 [IBIS]

Disease classification (adopted from Orphanet):

Parent Diseases: Leigh syndrome
 -Rare developmental defect during embryogenesis
 -Rare eye disease
 -Rare genetic disease
 -Rare neurologic disease
Neurometabolic disease
 -Rare genetic disease
 -Rare neurologic disease

Comment:

Mitochondrial Complex IV [cytochrome c oxidase (COX)] deficiency is one of the most common respiratory chain defects in humans. The clinical phenotypes associated with COX deficiency include liver disease, cardiomyopathy and Leigh syndrome, a neurodegenerative disorder characterized by bilateral high signal lesions in the brainstem and basal ganglia. COX deficiency can result from mutations affecting many different mitochondrial proteins. The French-Canadian variant of COX-deficient Leigh syndrome is unique to the Saguenay-Lac-Saint-Jean region of Québec and is caused by a founder mutation in the LRPPRC gene. This encodes the leucine-rich pentatricopeptide repeat domain protein (LRPPRC), which is involved in post-transcriptional regulation of mitochondrial gene expression (PMID:26510951). Saguenay-Lac-Saint-Jean (SLSJ) cytochrome oxidase (COX) deficiency (LS French-Canadian type [LSFC] [MIM 220111]), an autosomal recessive form of congenital lactic acidosis, presents with developmental delay and hypotonia. It is an LS variant that is found in a geographically isolated region of Quebec and that occurs in 1/2,178 live births. Patients with LSFC show a phenotype similar to that of patients with LS, but the two groups differ in clinical presentation. Two LRPPRC mutations are reported to cause SLSJ-COX: A354V, which accounted for all but one mutant allele in the original series, and C1277Xdel8. Heterozygote screening for A354V is now routinely offered to couples with Saguenay-Lac Saint-Jean ancestry.The median age for the first detected manifestation of the disease was 5 months (PMID:21266382).

Symptom Information: Sort by abundance 

1
 (HPO:0000664) Synophrys Occasional [IBIS] 26% (n=38) 21266382 IBIS 112 / 7739
2
 (HPO:0000260) Wide anterior fontanel Frequent [IBIS] 58% (n=24) 21266382 IBIS 55 / 7739
3
 (HPO:0001955) Unexplained fevers 21266382 IBIS 7 / 7739
4
 (HPO:0004798) Recurrent infection of the gastrointestinal tract 21266382 IBIS 9 / 7739
5
 (HPO:0200117) Recurrent upper and lower respiratory tract infections 21266382 IBIS 4 / 7739
6
 (HPO:0002033) Poor suck Frequent [IBIS] 44% (n=36) 21266382 IBIS 37 / 7739
7
 (HPO:0000316) Hypertelorism 56% (n=32) 21266382 IBIS 644 / 7739
8
 (HPO:0000486) Strabismus Frequent [IBIS] 35% (n=40) 21266382 IBIS 576 / 7739
9
 (HPO:0002151) Increased serum lactate 26510951 IBIS 92 / 7739
10
 (HPO:0003128) Lactic acidosis Very frequent [IBIS] 11156535 IBIS 116 / 7739
11
 (HPO:0004902) Congenital lactic acidosis Very frequent [IBIS] 21266382 IBIS 2 / 7739
12
 (HPO:0004900) Severe lactic acidosis 26510951 IBIS 5 / 7739
13
 (HPO:0001942) Metabolic acidosis Occasional [IBIS] 17% (n=36) 21266382 IBIS 81 / 7739
14
 (HPO:0001950) Respiratory alkalosis 21266382 IBIS 7 / 7739
15
 (HPO:0001508) Failure to thrive Frequent [IBIS] 52% (n=44) 21266382 IBIS 454 / 7739
16
 (HPO:0003074) Hyperglycemia 21266382 IBIS 37 / 7739
17
 (HPO:0001943) Hypoglycemia Occasional [IBIS] 17% (n=36) 21266382 IBIS 131 / 7739
18
 (HPO:0001627) Abnormal heart morphology Frequent [IBIS] 26510951 IBIS 19 / 7739
19
 (HPO:0001638) Cardiomyopathy 26510951 IBIS 192 / 7739
20
 (HPO:0008972) Decreased activity of mitochondrial respiratory chain Very frequent [IBIS] 26510951 IBIS 34 / 7739
21
 (HPO:0001252) Muscular hypotonia Frequent [IBIS] 58% (n=36) 21266382 IBIS 990 / 7739
22
 (HPO:0008947) Infantile muscular hypotonia Very frequent [IBIS] 100% (n=43) 21266382 IBIS 482 / 7739
23
 (HPO:0001324) Muscle weakness 21266382 IBIS 859 / 7739
24
 (HPO:0003324) Generalized muscle weakness 26510951 IBIS 48 / 7739
25
 (HPO:0002490) Increased CSF lactate 26510951 IBIS 28 / 7739
26
 (HPO:0002352) Leukoencephalopathy 26510951 IBIS 32 / 7739
27
 (HPO:0001251) Ataxia Frequent [IBIS] 48% (n=33) 21266382 IBIS 413 / 7739
28
 (HPO:0002066) Gait ataxia 21266382 IBIS 327 / 7739
29
 (HPO:0001332) Dystonia 26510951 IBIS 197 / 7739
30
 (HPO:0001263) Global developmental delay Very frequent [IBIS] 100% (n=43) 21266382 IBIS 853 / 7739
31
 (HPO:0001270) Motor delay 21266382 IBIS 322 / 7739
32
 (HPO:0000750) Delayed speech and language development 21266382 IBIS 197 / 7739
33
 (HPO:0001337) Tremor Frequent [IBIS] 54% (n=35) 21266382 IBIS 200 / 7739
34
 (HPO:0002015) Dysphagia 26510951 IBIS 301 / 7739
35
 (HPO:0001250) Seizures Occasional [IBIS] 13% (n=44) 21266382 IBIS 1245 / 7739
36
 (HPO:0011220) Prominent forehead Frequent [IBIS] 88% (n=40) 21266382 IBIS 137 / 7739
37
 (HPO:0001338) Partial agenesis of the corpus callosum 26510951 IBIS 22 / 7739
38
 (HPO:0002553) Highly arched eyebrow Frequent [IBIS] 58% (n=40) 21266382 IBIS 92 / 7739
39
 (HPO:0001007) Hirsutism Frequent [IBIS] 54% (n=39) 21266382 IBIS 91 / 7739
40
 (HPO:0000998) Hypertrichosis 21266382 IBIS 52 / 7739
41
 (HPO:0000815) Hypergonadotropic hypogonadism 21266382 IBIS 48 / 7739
42
 (HPO:0004673) Decreased facial expression 21266382 IBIS 5 / 7739
43
 (HPO:0011800) Midface retrusion Very frequent [IBIS] 90% (n=39) 21266382 IBIS 221 / 7739
44
 (HPO:0000431) Wide nasal bridge Frequent [IBIS] 87% (n=38) 21266382 IBIS 290 / 7739
45
 (HPO:0002401) Stroke-like episodes 10072055 IBIS 10 / 7739
46
 (HPO:0002789) Tachypnea 21266382 IBIS 48 / 7739
47
 (HPO:0003688) Decreased activity of cytochrome C oxidase in muscle tissue Very frequent [IBIS] 26510951 IBIS 20 / 7739
48
 (HPO:0012443) Abnormality of brain morphology Frequent [IBIS] 26510951 IBIS 45 / 7739
49
 (HPO:0007305) CNS demyelination 26510951 IBIS 21 / 7739
50
 (HPO:0001320) Cerebellar vermis hypoplasia 26510951 IBIS 57 / 7739
51
 (HPO:0012758) Neurodevelopmental delay 26510951 IBIS 949 / 7739
52
 (HPO:0002126) Polymicrogyria 26510951 IBIS 64 / 7739
53
 (MedDRA:10050111) Cardiomyopathy neonatal Frequent [IBIS] 26510951 IBIS 1 / 7739
54
 (MedDRA:10028154) Multi-organ failure Rare [IBIS] 3% (n=36) 21266382 IBIS 3 / 7739
55
 (MedDRA:10044403) Transient tachypnoea of the newborn Frequent [IBIS] 47% (n=36) 21266382 IBIS 1 / 7739
56
 (OMIM) Cytochrome c oxidase deficiency Very frequent [IBIS] 26510951 IBIS 2 / 7739
57
 (OMIM) Decreased cytochrome C oxidase activity 26510951 IBIS 2 / 7739
58
 (OMIM) Decreased cytochrome c oxidase activity in skin fibroblasts, liver, and skeletal muscle 26510951 IBIS 1 / 7739
59
 (OMIM) Hyperglycemia during crises 21266382 IBIS 1 / 7739
60
 (OMIM) Hyperlactatemia 21266382 IBIS 3 / 7739
61
 (OMIM) Metabolic crises 21266382 IBIS 2 / 7739
62
 (OMIM) Transient tachypnea of the newborn 21266382 IBIS 1 / 7739
63
 (OMIM) Unexpressive facies 21266382 IBIS 1 / 7739

Associated genes:

LRPPRC;

ClinVar (via SNiPA)

Gene symbol Variation Clinical significance Reference

Additional Information:

Description: (OMIM) The French Canadian type of Leigh syndrome is an autosomal recessive severe neurologic disorder with onset in infancy. Features include delayed psychomotor development, mental retardation, mild dysmorphic facial features, hypotonia, ataxia, and the development of lesions in the ...
Clinical Description OMIM Two clinical forms of cytochrome c oxidase (COX, complex IV) deficiency (220100) are recognized (DiMauro et al., 1990): a 'muscular' form in which marked weakness predominates, and a 'nonmuscular' form presenting with Leigh disease, a neurodegenerative condition of ...
Molecular genetics OMIM Lee et al. (2001) performed mutation screening of the COX7A2L gene (605771), which maps to chromosome 2, in patients with LSFC and in controls and found no functional mutations.

In 21 of 22 patients with LSFC, ...
Population genetics OMIM In the French Canadian population of the Saguenay-Lac-Saint-Jean region of Quebec province, De Braekeleer (1991) estimated the prevalence at birth of cytochrome c oxidase deficiency to be 1 in 2,473, giving a carrier frequency of 1 in 28. ...