# 220111

MITOCHONDRIAL COMPLEX IV DEFICIENCY, NUCLEAR TYPE 5; MC4DN5


Alternative titles; symbols

CYTOCHROME c OXIDASE DEFICIENCY, FRENCH CANADIAN TYPE
LEIGH SYNDROME, FRENCH CANADIAN TYPE; LSFC
COX DEFICIENCY, FRENCH CANADIAN TYPE
COX DEFICIENCY, SAGUENAY-LAC-SAINT-JEAN TYPE
LEIGH SYNDROME, SAGUENAY-LAC-SAINT-JEAN TYPE


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
2p21 Mitochondrial complex IV deficiency, nuclear type 5, (French-Canadian) 220111 AR 3 LRPPRC 607544
Clinical Synopsis
 
Phenotypic Series
 

INHERITANCE
- Autosomal recessive
GROWTH
Other
- Failure to thrive
HEAD & NECK
Head
- Microcephaly
- Prominent forehead
Face
- Dysmorphic features
- Midface hypoplasia
- Mask-like facies
Eyes
- Hypertelorism
- Strabismus
- Arched eyebrows
Nose
- Anteverted nares
- Wide nasal bridge
CARDIOVASCULAR
Heart
- Hypertrophic cardiomyopathy (in some patients)
RESPIRATORY
- Transient tachypnea of the newborn
- Abnormal breathing patterns
ABDOMEN
Liver
- Liver biopsy shows increased lipid droplets (microvesicular steatosis)
- Decreased cytochrome c oxidase activity
Gastrointestinal
- Dysphagia
- Poor feeding
- Tube feeding
SKIN, NAILS, & HAIR
Hair
- Low frontal hairline
- Arched eyebrows
- Hirsutism
MUSCLE, SOFT TISSUES
- Hypotonia
NEUROLOGIC
Central Nervous System
- Developmental delay
- Psychomotor retardation
- Language delay
- Hypotonia
- Ataxia
- Tremor
- Seizures (less common)
- Increased CSF lactate
- Neurologic crises with coma (in some patients)
- Lesions in basal ganglia, brainstem, cerebellum, thalamus, spinal cord
- Leigh syndrome
- Lesions characterized by demyelination, necrosis, gliosis, spongiosis, and capillary proliferation
METABOLIC FEATURES
- Lactic acidosis
- Hypoglycemia
- Metabolic crises
- Hyperglycemia during crises
LABORATORY ABNORMALITIES
- Increased serum lactate
- Increased CSF lactate
- Decreased cytochrome c oxidase activity in skin fibroblasts, liver, and skeletal muscle
MISCELLANEOUS
- Onset in infancy
- Death usually occurs by age 2 years
- Death often occurs during metabolic/acidotic crisis
- First described in the geographically isolated Saguenay-Lac-Saint-Jean region of Quebec, Canada
- Incidence of 1 in 2,000 in Saguenay-Lac-Saint-Jean region
MOLECULAR BASIS
- Caused by mutation in the leucine-rich PPR motif-containing protein gene (LRPPRC, 607544.0001)
Mitochondrial complex IV deficiency, nuclear-type - PS220110 - 23 Entries
Location Phenotype Inheritance Phenotype
mapping key
Phenotype
MIM number
Gene/Locus Gene/Locus
MIM number
1q42.2 Mitochondrial complex IV deficiency, nuclear type 13 AR 3 616501 COA6 614772
1q44 Mitochondrial complex IV deficiency, nuclear type 11 AR 3 619054 COX20 614698
2p21 Mitochondrial complex IV deficiency, nuclear type 5, (French-Canadian) AR 3 220111 LRPPRC 607544
2q11.2 ?Mitochondrial complex IV, deficiency, nuclear type 9 AR 3 616500 COA5 613920
7p21.3 ?Mitochondrial complex IV deficiency, nuclear type 21 AR 3 619065 COXFA4 603833
9q34.2 Mitochondrial complex IV deficiency, nuclear type 1 AR 3 220110 SURF1 185620
10q24.2 Mitochondrial complex IV deficiency, nuclear type 6 AR 3 615119 COX15 603646
11q13.1 ?Mitochondrial complex IV deficiency, nuclear type 15 AR 3 619059 COX8A 123870
12q13.12 ?Mitochondrial complex IV deficiency, nuclear type 10 AR 3 619053 COX14 614478
14q24.2 Mitochondrial complex IV deficiency, nuclear type 22 AR 3 619355 COX16 618064
14q32.33 Mitochondrial complex IV deficiency, nuclear type 17 AR 3 619061 APOPT1 616003
15q24.2 Mitochondrial complex IV deficiency, nuclear type 20 AR 3 619064 COX5A 603773
16p11.2 Mitochondrial complex IV deficiency, nuclear type 18 AR 3 619062 COX6A2 602009
16q24.1 Mitochondrial complex IV deficiency, nuclear type 16 AR 3 619060 COX4I1 123864
17p13.1 Mitochondrial complex IV deficiency, nuclear type 4 AR 3 619048 SCO1 603644
17p12 Mitochondrial complex IV deficiency, nuclear type 3 AR 3 619046 COX10 602125
17q21.2 ?Mitochondrial complex IV deficiency, nuclear type 14 AR 3 619058 COA3 614775
17q22 Mitochondrial complex IV deficiency, nuclear type 23 AR 3 620275 COX11 603648
17q23.3 Mitochondrial complex IV deficiency, nuclear type 8 AR 3 619052 TACO1 612958
19p13.2 Mitochondrial complex IV deficiency, nuclear type 12 AR 3 619055 PET100 614770
19q13.12 Mitochondrial complex IV deficiency, nuclear type 7 AR 3 619051 COX6B1 124089
20p11.23 ?Mitochondrial complex IV deficiency, nuclear type 19 AR 3 619063 PET117 614771
22q13.33 Mitochondrial complex IV deficiency, nuclear type 2 AR 3 604377 SCO2 604272

TEXT

A number sign (#) is used with this entry because of evidence that mitochondrial complex IV deficiency nuclear type 5 (MC4DN5), also known as the French Canadian type of Leigh syndrome, is caused by homozygous or compound heterozygous mutation in the LRPPRC gene (607544) on chromosome 2p21.


Description

Mitochondrial complex IV deficiency nuclear type 5 (MC4DN5) is an autosomal recessive severe metabolic multisystemic disorder with onset in infancy. Features include delayed psychomotor development, impaired intellectual development with speech delay, mild dysmorphic facial features, hypotonia, ataxia, and seizures. There is increased serum lactate and episodic hypoglycemia. Some patients may have cardiomyopathy, abnormal breathing, or liver abnormalities, reflecting systemic involvement. Brain imaging shows lesions in the brainstem and basal ganglia, consistent with a diagnosis of Leigh syndrome (see 256000). Affected individuals tend to have episodic metabolic and/or neurologic crises in early childhood, which often lead to early death (summary by Debray et al., 2011).

For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see 220110.


Clinical Features

In the Saguenay-Lac-Saint-Jean (SLSJ) region of Quebec province in Canada, Merante et al. (1993) described a biochemically distinct form of COX deficiency presenting as Leigh syndrome. Thirty-four children were observed to have a similar phenotype consisting of developmental delay, hypotonia, mild facial dysmorphism, chronic well-compensated metabolic acidosis, and high mortality due to episodes of severe acidosis and coma. Enzyme activity was close to normal in kidney and heart, 50% of normal in fibroblasts and skeletal muscle, and nearly absent in brain and liver. The deficiency of enzyme activity appeared to result from a failure to assemble an active enzyme complex. The cDNA sequences of cytochrome oxidase subunits VIa and VIIa were normal. Merante et al. (1993) demonstrated that the underlying defect was deficiency of COX, which was particularly severe in the liver.

Morin et al. (1993) described the clinical findings of 15 of the 34 patients referred to by Merante et al. (1993) who had biochemical evidence of COX deficiency. Fifteen patients in whom clinical findings were reported in detail were 6 months to 11 years of age; 11 children died in episodes of fulminant metabolic acidosis. These patients had elevated blood and cerebrospinal fluid lactate levels, decreased blood bicarbonate levels, and normal blood pH. Characteristic changes of Leigh disease were found in the central nervous system and microvesicular steatosis was found in the liver in all affected patients in whom postmortem examination was performed. Merante et al. (1993) found that the severity of the biochemical defect varied greatly in different tissues. The activity of COX in skin fibroblasts, amniocytes, and skeletal muscle was 50% of normal, while in kidney and heart it was close to normal. Brain and liver, on the other hand, had very low activities. The deficiency of activity appeared to result from a failure of assembly of the cytochrome oxidase complex in liver, but levels of mRNA for both mitochondrially encoded and nuclear-encoded subunits in liver and skin fibroblasts were found to be the same as those in controls. The cDNA sequence of the liver-specific cytochrome oxidase subunits VIa and VIIa were determined in samples from patient liver and skin fibroblasts and showed normal coding sequence. Segregation analysis was consistent with autosomal recessive inheritance.

Debray et al. (2011) retrospectively reviewed the clinical course of 56 patients with genetically confirmed French Canadian Leigh syndrome. The median age at onset was 5 months, and patients presented with neonatal distress, psychomotor delay, failure to thrive, ataxia, and acute metabolic acidosis. Other features during the neonatal period included hypotonia (58%), transient tachypnea of the newborn (47%), poor sucking (44%), tremor (28%), and hypoglycemia (17%). There were mild craniofacial features such as prominent forehead, midfacial hypoplasia, broad nasal bridge, hypertelorism, hirsutism, and arched eyebrows. All had developmental and language delay. Older ambulatory patients had truncal ataxia with wide-based gait and mild intention tremor. Most (90%) had 1 or more episodes of acute metabolic and/or neurologic decompensation, most of which (82%) resulted in death at a median age of 1.6 years. Metabolic crises were often associated with an infectious illness and were characterized by increased serum lactate, hyperglycemia, hypotonia, coma, liver dysfunction, shock, respiratory distress, and multiorgan failure. Neurologic crises were characterized by hypotonia, ataxia, coma, abnormal breathing patterns, seizures, and stroke-like episodes. There was a higher incidence of these acute episodes in patients with LRPPC mutations compared to patients with COX deficiency and Leigh syndrome due to SURF1 (185620) mutations (see 220110).

Olahova et al. (2015) reported 10 patients from 7 unrelated families that were not of French Canadian origin who had a severe neurodevelopmental disorder associated with biallelic LRPPRC mutations. Most presented at birth with lactic acidosis, hypotonia, and severely delayed psychomotor development with absent speech, although a few patients had normal early development with episodic decompensation and developmental regression associated with infection. A few patients had mild nonspecific dysmorphic features. Six patients died in infancy or early childhood. Those who survived showed variable neurologic features, including dystonia, ataxia, dysphagia, strabismus, and seizures. Neuroimaging in 2 patients showed features consistent with Leigh syndrome, but lesions were absent in other patients. Three had a striking leukoencephalopathy and 4 had cerebral malformations, such as cerebellar hypoplasia, gyral abnormalities, and hippocampal abnormalities. Other features included hypertrophic cardiomyopathy (in 2 patients), hypospadias (2 patients), anteriorly placed anus (1 patient), polysyndactyly (1 patient), and complex congenital heart disease (1 patient). All patients tested had variably decreased complex IV activity in fibroblasts and/or muscle tissue (range 3 to 70% residual activity).


Inheritance

The transmission pattern of MC4DN5 in the families reported by Olahova et al. (2015) was consistent with autosomal recessive inheritance.


Mapping

To identify the gene involved in COX deficiency in the Saguenay-Lac-Saint-Jean region, Lee et al. (1998) performed linkage disequilibrium mapping with a 318-marker genomewide scan using DNA from 14 affected individuals and their parents. One marker on chromosome 2 showed significant linkage disequilibrium. Further testing with additional affected individuals and additional markers spanning approximately 8 to 10 cM and observation of recombination events narrowed the SLSJ cytochrome oxidase deficiency critical region to approximately 1 to 2 cM.

Lee et al. (2001) performed a genomewide linkage disequilibrium scan and localized the Saguenay-Lac-Saint-Jean COX deficiency locus to 2p16. By identifying a common ancestral haplotype, they limited the critical region to approximately 2 cM between D2S119 and D2S2174.


Molecular Genetics

In 21 of 22 patients with LSFC, Mootha et al. (2003) identified a homozygous mutation in the LRPPRC gene (607544.0001). The remaining patient was a compound heterozygote; see 607544.0001.

In 10 patients from 7 unrelated families with LSFC who were not of French Canadian origin, Olahova et al. (2015) identified 5 different biallelic mutations in the LRPPRC gene (607544.0003-607544.0007). Patients from 4 unrelated families of Indian or Pakistani origin were homozygous for the same mutation (607544.0003). The mutations were found by whole-exome sequencing or candidate gene sequencing and segregated with the disorder in the families. Studies of fibroblast and muscle tissue from 3 patients showed decreased levels of the LRPPRC protein compared to controls, as well as a significant decrease in the basal oxygen consumption rate. There was almost complete loss of complex IV subunits as well as variable loss of other mitochondrial respiratory subunits, particularly complex I, and decreased levels of steady-state mitochondrial mRNA in patient fibroblasts and muscle tissue.

Exclusion Studies

Lee et al. (2001) performed mutation screening of the COX7A2L gene (605771), which maps to chromosome 2, in patients with MC4DN5 and in controls and found no functional mutations.


Pathogenesis

Sasarman et al. (2010) found that mutant LRPPRC was targeted normally to the mitochondrial compartment in immortalized LSFC patient fibroblasts, but that LRPPRC protein content was reduced. In vitro assays revealed that COX activity was reduced in LSFC patient fibroblasts compared with controls. Patient fibroblasts also showed reduced amounts of mitochondrial-encoded COX subunits I (MTCO1; 516030) and II (MTCO2; 516040), with a smaller decrease in the level of nuclear-encoded complex IV. LSFC patient fibroblasts showed reduced steady-state levels of mitochondrial mRNAs and had a defect in mitochondrial protein synthesis. Mitochondrial rRNAs and tRNAs were normal in LSFC fibroblasts. Knockdown of LRPPRC in control fibroblasts via siRNA replicated the generalized assembly defect in oxidative phosphorylation complexes. Sasarman et al. (2010) observed that COX mRNAs appeared to be more sensitive than other mRNAs to reduced LRPPRC content in LSFC fibroblasts.


Population Genetics

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.

Morin et al. (1993) estimated the incidence of cytochrome c oxidase deficiency at 1 in 2,063 live births between 1979 and 1990, giving a carrier rate of 1 in 23 among inhabitants of the SLSJ region. The genealogic reconstruction of 54 obligate carriers identified 26 ancestors common to all of them. Of these, 22 were 17th-century Europeans, suggesting that the COX-deficient gene was introduced into the French Canadian population by early settlers.


History

Two clinical forms of cytochrome c oxidase deficiency 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 the brainstem, cerebellum, and basal ganglia, with symmetric, well-demarcated regions of necrosis, gliosis, and vascular proliferation (van Erven et al., 1987). Leigh disease can also result from other inborn errors of energy metabolism, such as pyruvate dehydrogenase deficiency (266150), complex I deficiency (252010), and mutation in a mitochondrial DNA gene for complex V (516060).


REFERENCES

  1. De Braekeleer, M. Hereditary disorders in Saguenay-Lac-Saint-Jean (Quebec, Canada). Hum. Hered. 41: 141-146, 1991. [PubMed: 1937486, related citations] [Full Text]

  2. Debray, F. G., Morin, C., Janvier, A., Villeneuve, J., Maranda, B., Laframboise, R., Lacroix, J., Decarie, J.-C., Robitaille, Y., Lambert, M., Robinson, B. H., Mitchell, G. A. LRPPRC mutations cause a phenotypically distinct form of Leigh syndrome with cytochrome c oxidase deficiency. J. Med. Genet. 48: 183-189, 2011. [PubMed: 21266382, related citations] [Full Text]

  3. DiMauro, S., Lombes, A., Nakase, H., Mita, S., Fabrizi, G. M., Tritschler, H.-J., Bonilla, E., Miranda, A. F., DeVivo, D. C., Schon, E. A. Cytochrome c oxidase deficiency. Pediat. Res. 28: 536-541, 1990. [PubMed: 2175026, related citations] [Full Text]

  4. Lee, H. R. N., Rioux, J. D., Daly, M. J., Lander, E. S., Hudson, T. J., Morin, C. C., Robinson, B. H. Genetic mapping of Saguenay-Lac-Saint-Jean cytochrome oxidase deficiency. (Abstract) Am. J. Hum. Genet. 63: A296 only, 1998.

  5. Lee, N., Daly, M. J., Delmonte, T., Lander, E. S., Xu, F., Hudson, T. J., Mitchell, G. A., Morin, C. C., Robinson, B. H., Rioux, J. D. A genomewide linkage-disequilibrium scan localizes the Saguenay-Lac-Saint-Jean cytochrome oxidase deficiency to 2p16. Am. J. Hum. Genet. 68: 397-409, 2001. [PubMed: 11156535, images, related citations] [Full Text]

  6. Merante, F., Petrova-Benedict, R., MacKay, N., Mitchell, G., Lambert, M., Morin, C., De Braekeleer, M., Laframboise, R., Gagne, R., Robinson, B. H. A biochemically distinct form of cytochrome oxidase (COX) deficiency in the Saguenay-Lac-Saint-Jean region of Quebec. Am. J. Hum. Genet. 53: 481-487, 1993. [PubMed: 8392290, related citations]

  7. Mootha, V. K., Lepage, P., Miller, K., Bunkenborg, J., Reich, M., Hjerrild, M., Delmonte, T., Villeneuve, A., Sladek, R., Xu, F., Mitchell, G. A., Morin, C., Mann, M., Hudson, T. J., Robinson, B., Rioux, J. D., Lander, E. S. Identification of a gene causing human cytochrome c oxidase deficiency by integrative genomics. Proc. Nat. Acad. Sci. 100: 605-610, 2003. [PubMed: 12529507, images, related citations] [Full Text]

  8. Morin, C., Mitchell, G., Larochelle, J., Lambert, M., Ogier, H., Robinson, B. H., De Braekeleer, M. Clinical, metabolic, and genetic aspects of cytochrome c oxidase deficiency in Saguenay-Lac-Saint-Jean. Am. J. Hum. Genet. 53: 488-496, 1993. [PubMed: 8392291, related citations]

  9. Olahova, M., Hardy, S. A., Hall, J., Yarham, J. W., Haack, T. B., Wilson, W. C., Alston, C. L., He, L., Aznauryan, E., Brown, R. M., Brown, G. K., Morris, A. A. M., and 14 others. LRPPRC mutations cause early-onset multisystem mitochondrial disease outside of the French-Canadian population. Brain 138: 3503-3519, 2015. [PubMed: 26510951, images, related citations] [Full Text]

  10. Sasarman, F., Brunel-Guitton, C., Antonicka, H., Wai, T., Shoubridge, E. A., LSFC Consortium. LRPPRC and SLIRP interact in a ribonucleoprotein complex that regulates posttranscriptional gene expression in mitochondria. Molec. Biol. Cell 21: 1315-1323, 2010. [PubMed: 20200222, images, related citations] [Full Text]

  11. van Erven, P. M. M., Cillessen, J. P. M., Eekhoff, E. M. W., Gabreels, F. J. M., Doesburg, W. H., Lemmens, W. A. J. G., Slooff, J. L., Renier, W. O., Ruitenbeek, W. Leigh syndrome, a mitochondrial encephalo(myo)pathy: a review of the literature. Clin. Neurol. Neurosurg. 89: 217-230, 1987. [PubMed: 3319345, related citations] [Full Text]


Cassandra L. Kniffin - updated : 10/23/2020
Cassandra L. Kniffin - updated : 12/2/2015
Patricia A. Hartz - updated : 5/11/2015
Cassandra L. Kniffin - updated : 12/1/2011
Cassandra L. Kniffin - reorganized : 7/10/2003
Victor A. McKusick - updated : 2/12/2003
Victor A. McKusick - updated : 2/24/1999
Victor A. McKusick - updated : 11/30/1998
Creation Date:
Victor A. McKusick : 8/30/1993
carol : 11/02/2020
ckniffin : 10/29/2020
carol : 10/23/2020
carol : 10/15/2020
carol : 08/03/2020
carol : 03/15/2018
alopez : 12/03/2015
ckniffin : 12/2/2015
mgross : 5/11/2015
carol : 12/5/2011
ckniffin : 12/1/2011
ckniffin : 12/1/2011
terry : 10/26/2011
terry : 2/22/2005
carol : 7/10/2003
ckniffin : 7/10/2003
ckniffin : 7/10/2003
mgross : 2/14/2003
mgross : 2/14/2003
terry : 2/12/2003
carol : 3/26/2001
mcapotos : 3/12/2001
carol : 10/24/2000
carol : 9/29/1999
carol : 3/22/1999
terry : 2/24/1999
alopez : 12/8/1998
alopez : 11/30/1998
carol : 7/13/1996
davew : 6/1/1994
mimadm : 3/11/1994
carol : 10/18/1993
carol : 9/8/1993
carol : 8/30/1993

# 220111

MITOCHONDRIAL COMPLEX IV DEFICIENCY, NUCLEAR TYPE 5; MC4DN5


Alternative titles; symbols

CYTOCHROME c OXIDASE DEFICIENCY, FRENCH CANADIAN TYPE
LEIGH SYNDROME, FRENCH CANADIAN TYPE; LSFC
COX DEFICIENCY, FRENCH CANADIAN TYPE
COX DEFICIENCY, SAGUENAY-LAC-SAINT-JEAN TYPE
LEIGH SYNDROME, SAGUENAY-LAC-SAINT-JEAN TYPE


SNOMEDCT: 718219002;   ORPHA: 70472;   DO: 0111180;  


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
2p21 Mitochondrial complex IV deficiency, nuclear type 5, (French-Canadian) 220111 Autosomal recessive 3 LRPPRC 607544

TEXT

A number sign (#) is used with this entry because of evidence that mitochondrial complex IV deficiency nuclear type 5 (MC4DN5), also known as the French Canadian type of Leigh syndrome, is caused by homozygous or compound heterozygous mutation in the LRPPRC gene (607544) on chromosome 2p21.


Description

Mitochondrial complex IV deficiency nuclear type 5 (MC4DN5) is an autosomal recessive severe metabolic multisystemic disorder with onset in infancy. Features include delayed psychomotor development, impaired intellectual development with speech delay, mild dysmorphic facial features, hypotonia, ataxia, and seizures. There is increased serum lactate and episodic hypoglycemia. Some patients may have cardiomyopathy, abnormal breathing, or liver abnormalities, reflecting systemic involvement. Brain imaging shows lesions in the brainstem and basal ganglia, consistent with a diagnosis of Leigh syndrome (see 256000). Affected individuals tend to have episodic metabolic and/or neurologic crises in early childhood, which often lead to early death (summary by Debray et al., 2011).

For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see 220110.


Clinical Features

In the Saguenay-Lac-Saint-Jean (SLSJ) region of Quebec province in Canada, Merante et al. (1993) described a biochemically distinct form of COX deficiency presenting as Leigh syndrome. Thirty-four children were observed to have a similar phenotype consisting of developmental delay, hypotonia, mild facial dysmorphism, chronic well-compensated metabolic acidosis, and high mortality due to episodes of severe acidosis and coma. Enzyme activity was close to normal in kidney and heart, 50% of normal in fibroblasts and skeletal muscle, and nearly absent in brain and liver. The deficiency of enzyme activity appeared to result from a failure to assemble an active enzyme complex. The cDNA sequences of cytochrome oxidase subunits VIa and VIIa were normal. Merante et al. (1993) demonstrated that the underlying defect was deficiency of COX, which was particularly severe in the liver.

Morin et al. (1993) described the clinical findings of 15 of the 34 patients referred to by Merante et al. (1993) who had biochemical evidence of COX deficiency. Fifteen patients in whom clinical findings were reported in detail were 6 months to 11 years of age; 11 children died in episodes of fulminant metabolic acidosis. These patients had elevated blood and cerebrospinal fluid lactate levels, decreased blood bicarbonate levels, and normal blood pH. Characteristic changes of Leigh disease were found in the central nervous system and microvesicular steatosis was found in the liver in all affected patients in whom postmortem examination was performed. Merante et al. (1993) found that the severity of the biochemical defect varied greatly in different tissues. The activity of COX in skin fibroblasts, amniocytes, and skeletal muscle was 50% of normal, while in kidney and heart it was close to normal. Brain and liver, on the other hand, had very low activities. The deficiency of activity appeared to result from a failure of assembly of the cytochrome oxidase complex in liver, but levels of mRNA for both mitochondrially encoded and nuclear-encoded subunits in liver and skin fibroblasts were found to be the same as those in controls. The cDNA sequence of the liver-specific cytochrome oxidase subunits VIa and VIIa were determined in samples from patient liver and skin fibroblasts and showed normal coding sequence. Segregation analysis was consistent with autosomal recessive inheritance.

Debray et al. (2011) retrospectively reviewed the clinical course of 56 patients with genetically confirmed French Canadian Leigh syndrome. The median age at onset was 5 months, and patients presented with neonatal distress, psychomotor delay, failure to thrive, ataxia, and acute metabolic acidosis. Other features during the neonatal period included hypotonia (58%), transient tachypnea of the newborn (47%), poor sucking (44%), tremor (28%), and hypoglycemia (17%). There were mild craniofacial features such as prominent forehead, midfacial hypoplasia, broad nasal bridge, hypertelorism, hirsutism, and arched eyebrows. All had developmental and language delay. Older ambulatory patients had truncal ataxia with wide-based gait and mild intention tremor. Most (90%) had 1 or more episodes of acute metabolic and/or neurologic decompensation, most of which (82%) resulted in death at a median age of 1.6 years. Metabolic crises were often associated with an infectious illness and were characterized by increased serum lactate, hyperglycemia, hypotonia, coma, liver dysfunction, shock, respiratory distress, and multiorgan failure. Neurologic crises were characterized by hypotonia, ataxia, coma, abnormal breathing patterns, seizures, and stroke-like episodes. There was a higher incidence of these acute episodes in patients with LRPPC mutations compared to patients with COX deficiency and Leigh syndrome due to SURF1 (185620) mutations (see 220110).

Olahova et al. (2015) reported 10 patients from 7 unrelated families that were not of French Canadian origin who had a severe neurodevelopmental disorder associated with biallelic LRPPRC mutations. Most presented at birth with lactic acidosis, hypotonia, and severely delayed psychomotor development with absent speech, although a few patients had normal early development with episodic decompensation and developmental regression associated with infection. A few patients had mild nonspecific dysmorphic features. Six patients died in infancy or early childhood. Those who survived showed variable neurologic features, including dystonia, ataxia, dysphagia, strabismus, and seizures. Neuroimaging in 2 patients showed features consistent with Leigh syndrome, but lesions were absent in other patients. Three had a striking leukoencephalopathy and 4 had cerebral malformations, such as cerebellar hypoplasia, gyral abnormalities, and hippocampal abnormalities. Other features included hypertrophic cardiomyopathy (in 2 patients), hypospadias (2 patients), anteriorly placed anus (1 patient), polysyndactyly (1 patient), and complex congenital heart disease (1 patient). All patients tested had variably decreased complex IV activity in fibroblasts and/or muscle tissue (range 3 to 70% residual activity).


Inheritance

The transmission pattern of MC4DN5 in the families reported by Olahova et al. (2015) was consistent with autosomal recessive inheritance.


Mapping

To identify the gene involved in COX deficiency in the Saguenay-Lac-Saint-Jean region, Lee et al. (1998) performed linkage disequilibrium mapping with a 318-marker genomewide scan using DNA from 14 affected individuals and their parents. One marker on chromosome 2 showed significant linkage disequilibrium. Further testing with additional affected individuals and additional markers spanning approximately 8 to 10 cM and observation of recombination events narrowed the SLSJ cytochrome oxidase deficiency critical region to approximately 1 to 2 cM.

Lee et al. (2001) performed a genomewide linkage disequilibrium scan and localized the Saguenay-Lac-Saint-Jean COX deficiency locus to 2p16. By identifying a common ancestral haplotype, they limited the critical region to approximately 2 cM between D2S119 and D2S2174.


Molecular Genetics

In 21 of 22 patients with LSFC, Mootha et al. (2003) identified a homozygous mutation in the LRPPRC gene (607544.0001). The remaining patient was a compound heterozygote; see 607544.0001.

In 10 patients from 7 unrelated families with LSFC who were not of French Canadian origin, Olahova et al. (2015) identified 5 different biallelic mutations in the LRPPRC gene (607544.0003-607544.0007). Patients from 4 unrelated families of Indian or Pakistani origin were homozygous for the same mutation (607544.0003). The mutations were found by whole-exome sequencing or candidate gene sequencing and segregated with the disorder in the families. Studies of fibroblast and muscle tissue from 3 patients showed decreased levels of the LRPPRC protein compared to controls, as well as a significant decrease in the basal oxygen consumption rate. There was almost complete loss of complex IV subunits as well as variable loss of other mitochondrial respiratory subunits, particularly complex I, and decreased levels of steady-state mitochondrial mRNA in patient fibroblasts and muscle tissue.

Exclusion Studies

Lee et al. (2001) performed mutation screening of the COX7A2L gene (605771), which maps to chromosome 2, in patients with MC4DN5 and in controls and found no functional mutations.


Pathogenesis

Sasarman et al. (2010) found that mutant LRPPRC was targeted normally to the mitochondrial compartment in immortalized LSFC patient fibroblasts, but that LRPPRC protein content was reduced. In vitro assays revealed that COX activity was reduced in LSFC patient fibroblasts compared with controls. Patient fibroblasts also showed reduced amounts of mitochondrial-encoded COX subunits I (MTCO1; 516030) and II (MTCO2; 516040), with a smaller decrease in the level of nuclear-encoded complex IV. LSFC patient fibroblasts showed reduced steady-state levels of mitochondrial mRNAs and had a defect in mitochondrial protein synthesis. Mitochondrial rRNAs and tRNAs were normal in LSFC fibroblasts. Knockdown of LRPPRC in control fibroblasts via siRNA replicated the generalized assembly defect in oxidative phosphorylation complexes. Sasarman et al. (2010) observed that COX mRNAs appeared to be more sensitive than other mRNAs to reduced LRPPRC content in LSFC fibroblasts.


Population Genetics

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.

Morin et al. (1993) estimated the incidence of cytochrome c oxidase deficiency at 1 in 2,063 live births between 1979 and 1990, giving a carrier rate of 1 in 23 among inhabitants of the SLSJ region. The genealogic reconstruction of 54 obligate carriers identified 26 ancestors common to all of them. Of these, 22 were 17th-century Europeans, suggesting that the COX-deficient gene was introduced into the French Canadian population by early settlers.


History

Two clinical forms of cytochrome c oxidase deficiency 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 the brainstem, cerebellum, and basal ganglia, with symmetric, well-demarcated regions of necrosis, gliosis, and vascular proliferation (van Erven et al., 1987). Leigh disease can also result from other inborn errors of energy metabolism, such as pyruvate dehydrogenase deficiency (266150), complex I deficiency (252010), and mutation in a mitochondrial DNA gene for complex V (516060).


REFERENCES

  1. De Braekeleer, M. Hereditary disorders in Saguenay-Lac-Saint-Jean (Quebec, Canada). Hum. Hered. 41: 141-146, 1991. [PubMed: 1937486] [Full Text: https://doi.org/10.1159/000153992]

  2. Debray, F. G., Morin, C., Janvier, A., Villeneuve, J., Maranda, B., Laframboise, R., Lacroix, J., Decarie, J.-C., Robitaille, Y., Lambert, M., Robinson, B. H., Mitchell, G. A. LRPPRC mutations cause a phenotypically distinct form of Leigh syndrome with cytochrome c oxidase deficiency. J. Med. Genet. 48: 183-189, 2011. [PubMed: 21266382] [Full Text: https://doi.org/10.1136/jmg.2010.081976]

  3. DiMauro, S., Lombes, A., Nakase, H., Mita, S., Fabrizi, G. M., Tritschler, H.-J., Bonilla, E., Miranda, A. F., DeVivo, D. C., Schon, E. A. Cytochrome c oxidase deficiency. Pediat. Res. 28: 536-541, 1990. [PubMed: 2175026] [Full Text: https://doi.org/10.1203/00006450-199011000-00025]

  4. Lee, H. R. N., Rioux, J. D., Daly, M. J., Lander, E. S., Hudson, T. J., Morin, C. C., Robinson, B. H. Genetic mapping of Saguenay-Lac-Saint-Jean cytochrome oxidase deficiency. (Abstract) Am. J. Hum. Genet. 63: A296 only, 1998.

  5. Lee, N., Daly, M. J., Delmonte, T., Lander, E. S., Xu, F., Hudson, T. J., Mitchell, G. A., Morin, C. C., Robinson, B. H., Rioux, J. D. A genomewide linkage-disequilibrium scan localizes the Saguenay-Lac-Saint-Jean cytochrome oxidase deficiency to 2p16. Am. J. Hum. Genet. 68: 397-409, 2001. [PubMed: 11156535] [Full Text: https://doi.org/10.1086/318197]

  6. Merante, F., Petrova-Benedict, R., MacKay, N., Mitchell, G., Lambert, M., Morin, C., De Braekeleer, M., Laframboise, R., Gagne, R., Robinson, B. H. A biochemically distinct form of cytochrome oxidase (COX) deficiency in the Saguenay-Lac-Saint-Jean region of Quebec. Am. J. Hum. Genet. 53: 481-487, 1993. [PubMed: 8392290]

  7. Mootha, V. K., Lepage, P., Miller, K., Bunkenborg, J., Reich, M., Hjerrild, M., Delmonte, T., Villeneuve, A., Sladek, R., Xu, F., Mitchell, G. A., Morin, C., Mann, M., Hudson, T. J., Robinson, B., Rioux, J. D., Lander, E. S. Identification of a gene causing human cytochrome c oxidase deficiency by integrative genomics. Proc. Nat. Acad. Sci. 100: 605-610, 2003. [PubMed: 12529507] [Full Text: https://doi.org/10.1073/pnas.242716699]

  8. Morin, C., Mitchell, G., Larochelle, J., Lambert, M., Ogier, H., Robinson, B. H., De Braekeleer, M. Clinical, metabolic, and genetic aspects of cytochrome c oxidase deficiency in Saguenay-Lac-Saint-Jean. Am. J. Hum. Genet. 53: 488-496, 1993. [PubMed: 8392291]

  9. Olahova, M., Hardy, S. A., Hall, J., Yarham, J. W., Haack, T. B., Wilson, W. C., Alston, C. L., He, L., Aznauryan, E., Brown, R. M., Brown, G. K., Morris, A. A. M., and 14 others. LRPPRC mutations cause early-onset multisystem mitochondrial disease outside of the French-Canadian population. Brain 138: 3503-3519, 2015. [PubMed: 26510951] [Full Text: https://doi.org/10.1093/brain/awv291]

  10. Sasarman, F., Brunel-Guitton, C., Antonicka, H., Wai, T., Shoubridge, E. A., LSFC Consortium. LRPPRC and SLIRP interact in a ribonucleoprotein complex that regulates posttranscriptional gene expression in mitochondria. Molec. Biol. Cell 21: 1315-1323, 2010. [PubMed: 20200222] [Full Text: https://doi.org/10.1091/mbc.e10-01-0047]

  11. van Erven, P. M. M., Cillessen, J. P. M., Eekhoff, E. M. W., Gabreels, F. J. M., Doesburg, W. H., Lemmens, W. A. J. G., Slooff, J. L., Renier, W. O., Ruitenbeek, W. Leigh syndrome, a mitochondrial encephalo(myo)pathy: a review of the literature. Clin. Neurol. Neurosurg. 89: 217-230, 1987. [PubMed: 3319345] [Full Text: https://doi.org/10.1016/s0303-8467(87)80020-3]


Contributors:
Cassandra L. Kniffin - updated : 10/23/2020
Cassandra L. Kniffin - updated : 12/2/2015
Patricia A. Hartz - updated : 5/11/2015
Cassandra L. Kniffin - updated : 12/1/2011
Cassandra L. Kniffin - reorganized : 7/10/2003
Victor A. McKusick - updated : 2/12/2003
Victor A. McKusick - updated : 2/24/1999
Victor A. McKusick - updated : 11/30/1998

Creation Date:
Victor A. McKusick : 8/30/1993

Edit History:
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carol : 10/18/1993
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carol : 8/30/1993