Carnitine palmitoyltransferase II (CPT II) deficiency is a disorder of long-chain fatty-acid oxidation. The three clinical presentations are lethal neonatal form, severe infantile hepatocardiomuscular form, and myopathic form (which is usually mild and can manifest from infancy to adulthood). While the former two are severe multisystemic diseases characterized by liver failure with hypoketotic hypoglycemia, cardiomyopathy, seizures, and early death, the latter is characterized by exercise-induced muscle pain and weakness, sometimes associated with myoglobinuria. The myopathic form of CPT II deficiency is the most common disorder of lipid metabolism affecting skeletal muscle and the most frequent cause of hereditary myoglobinuria. Males are more likely to be affected than females.

Combined oxidative phosphorylation deficiency is an autosomal recessive multisystem disorder with variable manifestations resulting from a defect in the mitochondrial oxidative phosphorylation (OXPHOS) system. Onset occurs at or soon after birth, and features can include growth retardation, microcephaly, hypertonicity, axial hypotonia, encephalopathy, cardiomyopathy, and liver dysfunction. Death usually occurs in the first weeks or years of life (summary by Smits et al., 2011). Genetic Heterogeneity of Combined Oxidative Phosphorylation Deficiency See also COXPD2 (610498), caused by mutation in the MRPS16 gene (609204) on 10q22; COXPD3 (610505), caused by mutation in the TSFM gene (604723) on 12q14; COXPD4 (610678), caused by mutation in the TUFM gene (602389) on 16p11; COXPD5 (611719), caused by mutation in the MRPS22 gene (605810) on 3q23; COXPD6 (300816), caused by mutation in the AIFM1 gene (300169) on Xq26; COXPD7 (613559), caused by mutation in the MTRFR gene (613541) on 12q24; COXPD8 (614096), caused by mutation in the AARS2 gene (612035) on 6p21; COXPD9 (614582), caused by mutation in the MRPL3 gene (607118) on 3q22; COXPD10 (614702), caused by mutation in the MTO1 gene (614667) on 6q13; COXPD11 (614922), caused by mutation in the RMND1 gene (614917) on 6q25; COXPD12 (614924), caused by mutation in the EARS2 gene (612799) on 16p13; COXPD13 (614932), caused by mutation in the PNPT1 gene (610316) on 2p16; COXPD14 (614946), caused by mutation in the FARS2 gene (611592) on 6p25; COXPD15 (614947), caused by mutation in the MTFMT gene (611766) on 15q; COXPD16 (615395), caused by mutation in the MRPL44 gene (611849) on 2q36; COXPD17 (615440), caused by mutation in the ELAC2 gene (605367) on 17p11; COXPD18 (615578), caused by mutation in the SFXN4 gene (615564) on 10q26; COXPD19 (615595), caused by mutation in the LYRM4 gene (613311) on 6p25; COXPD20 (615917), caused by mutation in the VARS2 gene (612802) on 6p21; COXPD21 (615918), caused by mutation in the TARS2 gene (612805) on 1q21; COXPD22 (616045), caused by mutation in the ATP5A1 gene (164360) on 18q12; COXPD23 (616198), caused by mutation in the GTPBP3 (608536) gene on 19p13; COXPD24 (616239), caused by mutation in the NARS2 gene (612803) on 11q14; COXPD25 (616430), caused by mutation in the MARS2 gene (609728) on 2q33; COXPD26 (616539), caused by mutation in the TRMT5 gene (611023) on 14q23; COXPD27 (616672), caused by mutation in the CARS2 gene (612800) on 13q34; COXPD28 (616794), caused by mutation in the SLC25A26 gene (611037) on 3p14; COXPD29 (616811), caused by mutation in the TXN2 gene (609063) on 22q12; COXPD30 (616974), caused by mutation in the TRMT10C gene (615423) on 3q12; and COXPD31 (617228), caused by mutation in the MIPEP gene (602241) on 13q12; COXPD32 (617664), caused by mutation in the MRPS34 gene (611994) on 16q13; COXPD33 (617713), caused by mutation in the C1QBP gene (601269) on 17p13; and COXPD34 (617872), caused by mutation in the MRPS7 gene (611974) on 17q25; COXPD35 (617873), caused by mutation in the TRIT1 gene (617840) on 1p34; COXPD36 (617950), caused by mutation in the MRPS2 gene (611971) on 9q34; COXPD37 (618329), caused by mutation in the MICOS13 gene (616658) on 19p13; COXPD38 (618378), caused by mutation in the MRPS14 gene (611978) on 1q23; COXPD39 (618397), caused by mutation in the GFM2 gene (606544) on 5q13; COXPD40 (618835), caused by mutation in the QRSL1 gene (617209) on 6q21; COXPD41 (618838), caused by mutation in the GATB gene (603645) on 4q31; COXPD42 (618839), caused by mutation in the GATC gene (617210) on 12q24; COXPD43 (618851), caused by mutation in the TIMM22 gene (607251) on 17p13; COXPD44 (618855), caused by mutation in the FASTKD2 gene (612322) on 2q33; COXPD45 (618951), caused by mutation in the MRPL12 gene (602375) on 17q25; COXPD46 (618952), caused by mutation in the MRPS23 gene (611985) on 17q22; COXPD47 (618958), caused by mutation in the MRPS28 gene (611990) on 8q21; COXPD48 (619012), caused by mutation in the NSUN3 gene (617491) on 3q11; COXPD49 (619024), caused by mutation in the MIEF2 gene (615498) on 17p11; COXPD50 (619025), caused by mutation in the MRPS25 gene (611987) on 3p25; COXPD51 (619057), caused by mutation in the PTCD3 gene (614918) on 2p11; COXPD52 (619386), caused by mutation in the NFS1 gene (603485) on 20q11; COXPD53 (619423), caused by mutation in the C2ORF69 gene (619219) on 2q33; and COXPD54 (619737), caused by mutation in the PRORP gene (609947) on 14q13.; COXPD55 (619743), caused by mutation in the POLRMT gene (601778) on 19p13; COXPD56 (620139), caused by mutation in the TAMM41 gene (614948) on 3p25; COXPD57 (620167), caused by mutation in the CRLS1 gene (608188) on 20p12; COXPD58 (620451), caused by mutation in the TEFM gene (616422) on 17q11; and COXPD59 (620646), caused by mutation in the MRPL39 gene (611845) on 21q21.

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 is one of the few X-linked diseases in which a high proportion of heterozygous females manifest severe symptoms. The clinical spectrum of PDH deficiency is broad, ranging from fatal lactic acidosis in the newborn to chronic neurologic dysfunction with structural abnormalities in the central nervous system without systemic acidosis (Robinson et al., 1987; Brown et al., 1994). Genetic Heterogeneity of Pyruvate Dehydrogenase Complex Deficiency PDH deficiency can also be caused by mutation in other subunits of the PDH complex, including a form (PDHXD; 245349) caused by mutation in the component X gene (PDHX; 608769) on chromosome 11p13; a form (PDHBD; 614111) caused by mutation in the PDHB gene (179060) on chromosome 3p14; a form (PDHDD; 245348) caused by mutation in the DLAT gene (608770) on chromosome 11q23; a form (PDHPD; 608782) caused by mutation in the PDP1 gene (605993) on chromosome 8q22; and a form (PDHLD; 614462) caused by mutation in the LIAS gene (607031) on chromosome 4p14.