Identification of novel mutations in Spanish patients with muscle carnitine palmitoyltransferase II deficiency

Abstract

Carnitine palmitoyltransferase II (CPT II) deficiency is the most common recessively inherited disorder of lipid metabolism affecting skeletal muscle and the most frequent cause of hereditary myoglobinuria. We studied 5 Spanish patients with CPT II deficiency from four unrelated families. Four patients had the typical clinical phenotype of muscle CPT II deficiency with recurrent episodes of myoglobinuria, triggered by prolonged exercise, fasting, or fever, and marked elevation of creatine kinase values during metabolic crisis. One patient had exercise‐related myalgia, cramps and moderate elevation of serum CK values, but had never had myoglobinuria. Molecular analysis showed that three patients were heterozygous for the S113L mutation and one patient heterozygous for the P50H substitution. To identify the mutations in the other alleles of our patients we amplified and sequenced genomic DNA fragments encompassing the entire coding region and intron/exon boundaries of the CPT2 gene. We found the recently reported 178 insT/del 25 bp in one patient. Three novel mutations were identified: a Y120C substitution that leads to a nonconservative amino acid replacement; a 36‐38 insGC mutation that results in premature termination of the translation; and an I502T substitution that affects a conserved amino acid residue in the CPT II protein. Our data confirm the molecular heterogeneity of patients with CPT II deficiency, and suggest that the ethnic origin has to be taken into account before performing mutation analysis in these patients. Hum Mutat 15:579–580, 2000. © 2000 Wiley‐Liss, Inc.

Muscle Carnitine Palmitoyltransferase II Deficiency

“…[4][5][6] This mutation is known to be of Ashkenazi Jewish origin, 21 which might explain why it was found more frequently in the US study (Table 3). In addition, our group [4][5][6] and others 12,[20][21][22][23][24][25][26][27][28] have communicated at least 19 private mutations in patients with muscle CPT II deficiency (Figure 1). Exact genotypes of our patients are given in Table 2.…”

Muscle Carnitine Palmitoyltransferase II Deficiency

“…[4][5][6] This mutation is known to be of Ashkenazi Jewish origin, 21 which might explain why it was found more frequently in the US study (Table 3). In addition, our group [4][5][6] and others 12,[20][21][22][23][24][25][26][27][28] have communicated at least 19 private mutations in patients with muscle CPT II deficiency (Figure 1). Exact genotypes of our patients are given in Table 2.…”

Exome sequencing in Jewish and Arab patients with rhabdomyolysis reveals single-gene etiology in 43% of cases

“…Disorders of fatty acid metabolism: mutations in CPT2 are considered to be the most common monogenic cause for rhabdomyolysis [10, 18]. Mutations in CPT2 lead to carnitine palmitoyltransferase II (CPT2) deficiency, a metabolic disorder of long-chain fatty-acid oxidation [18].…”

“…Mutations in CPT2 lead to carnitine palmitoyltransferase II (CPT2) deficiency, a metabolic disorder of long-chain fatty-acid oxidation [18]. This syndrome has variable clinical presentations, which typically consist of one of the following three forms: 1) lethal neonatal form; 2) severe infantile hepato-cardio-muscular form; and 3) myopathic form.…”

Acute Renal Failure Secondary to an Unusual Familial Metabolic Myopathy

“…Taking into account these data, the variant c.110_111dup p.(Ser38Alafs*36) was classified as pathogenic using American College of Medical Genetics and Genomics (ACMG) guidelines [7]. The missense variant c.338C>T p.(Ser113Leu) has been described as the most common disease-causing variant in Spanish patients with CPT II deficiency in muscle [6]. This variant was predicted to be pathogenic by eleven prediction tools (BayesDel_addAF, DANN, DEOGEN2, EIGEN, FATHMM-MKL, M-CAP, MVP, MutationAssessor, MutationTaster, REVEL, and SIFT) and benign by 1 (PrimateAI).…”

Muscle Carnitine Palmitoyltransferase II Deficiency

“…[4][5][6] This mutation is known to be of Ashkenazi Jewish origin, 21 which might explain why it was found more frequently in the US study (Table 3). In addition, our group [4][5][6] and others 12,[20][21][22][23][24][25][26][27][28] have communicated at least 19 private mutations in patients with muscle CPT II deficiency (Figure 1). Exact genotypes of our patients are given in Table 2.…”

Exome sequencing in Jewish and Arab patients with rhabdomyolysis reveals single-gene etiology in 43% of cases

“…Disorders of fatty acid metabolism: mutations in CPT2 are considered to be the most common monogenic cause for rhabdomyolysis [10, 18]. Mutations in CPT2 lead to carnitine palmitoyltransferase II (CPT2) deficiency, a metabolic disorder of long-chain fatty-acid oxidation [18].…”

“…Mutations in CPT2 lead to carnitine palmitoyltransferase II (CPT2) deficiency, a metabolic disorder of long-chain fatty-acid oxidation [18]. This syndrome has variable clinical presentations, which typically consist of one of the following three forms: 1) lethal neonatal form; 2) severe infantile hepato-cardio-muscular form; and 3) myopathic form.…”

Acute Renal Failure Secondary to an Unusual Familial Metabolic Myopathy

“…Taking into account these data, the variant c.110_111dup p.(Ser38Alafs*36) was classified as pathogenic using American College of Medical Genetics and Genomics (ACMG) guidelines [7]. The missense variant c.338C>T p.(Ser113Leu) has been described as the most common disease-causing variant in Spanish patients with CPT II deficiency in muscle [6]. This variant was predicted to be pathogenic by eleven prediction tools (BayesDel_addAF, DANN, DEOGEN2, EIGEN, FATHMM-MKL, M-CAP, MVP, MutationAssessor, MutationTaster, REVEL, and SIFT) and benign by 1 (PrimateAI).…”

Muscle Carnitine Palmitoyltransferase II Deficiency

“…[4][5][6] This mutation is known to be of Ashkenazi Jewish origin, 21 which might explain why it was found more frequently in the US study (Table 3). In addition, our group [4][5][6] and others 12,[20][21][22][23][24][25][26][27][28] have communicated at least 19 private mutations in patients with muscle CPT II deficiency (Figure 1). Exact genotypes of our patients are given in Table 2.…”

Exome sequencing in Jewish and Arab patients with rhabdomyolysis reveals single-gene etiology in 43% of cases

“…Disorders of fatty acid metabolism: mutations in CPT2 are considered to be the most common monogenic cause for rhabdomyolysis [10, 18]. Mutations in CPT2 lead to carnitine palmitoyltransferase II (CPT2) deficiency, a metabolic disorder of long-chain fatty-acid oxidation [18].…”

“…Mutations in CPT2 lead to carnitine palmitoyltransferase II (CPT2) deficiency, a metabolic disorder of long-chain fatty-acid oxidation [18]. This syndrome has variable clinical presentations, which typically consist of one of the following three forms: 1) lethal neonatal form; 2) severe infantile hepato-cardio-muscular form; and 3) myopathic form.…”

Acute Renal Failure Secondary to an Unusual Familial Metabolic Myopathy

“…Taking into account these data, the variant c.110_111dup p.(Ser38Alafs*36) was classified as pathogenic using American College of Medical Genetics and Genomics (ACMG) guidelines [7]. The missense variant c.338C>T p.(Ser113Leu) has been described as the most common disease-causing variant in Spanish patients with CPT II deficiency in muscle [6]. This variant was predicted to be pathogenic by eleven prediction tools (BayesDel_addAF, DANN, DEOGEN2, EIGEN, FATHMM-MKL, M-CAP, MVP, MutationAssessor, MutationTaster, REVEL, and SIFT) and benign by 1 (PrimateAI).…”