Sengers Syndrome
A number sign (#) is used with this entry because Sengers syndrome, also known as cardiomyopathic mitochondrial DNA depletion syndrome-10 (MTDPS10), is caused by homozygous or compound heterozygous mutation in the AGK gene (610345) on chromosome 7q34.
For a discussion of genetic heterogeneity of autosomal recessive mtDNA depletion syndromes, see MTDPS1 (603041).
DescriptionSengers syndrome is an autosomal recessive mitochondrial disorder characterized by congenital cataracts, hypertrophic cardiomyopathy, skeletal myopathy, exercise intolerance, and lactic acidosis. Mental development is normal, but affected individuals may die early from cardiomyopathy (summary by Mayr et al., 2012). Skeletal muscle biopsies of 2 affected individuals showed severe mtDNA depletion (Calvo et al., 2012).
Clinical FeaturesIn 7 of 22 children in 3 unrelated sibships, Sengers et al. (1975) described congenital cataract and mitochondrial myopathy of skeletal and heart muscle. Cardiomyopathy of hypertrophic type dominated the clinical picture. Histologically, abnormality of mitochondria and storage of lipid and glycogen were found in both skeletal and heart muscle. When the patients performed submaximal exercise for 60 minutes, they developed lactic acidemia. All 3 families originated from the southeast region of the Netherlands.
Cruysberg et al. (1986) studied 12 patients from 6 unrelated families. The patients had bilateral and total cataract in the first weeks of life, underwent cataract surgery, and developed nystagmus and strabismus. They were mentally normal. Cardiomyopathy was progressive and the cause of premature death. Three of the 12 patients died in the neonatal period and 6 in early adulthood. The oldest living patient was 37 years old. The authors recommended that patients avoid heavy exercise. Lalive d'Epinay et al. (1986) described the disorder in 3 children from 2 unrelated families in Switzerland. Infantile cataract, which was the primary symptom at the age of 3 months, progressed quickly and necessitated surgery. Muscular hypotonia and delayed motor development were conspicuous. A distinctive feature was the development of marked lactic acidemia on slight muscular exercise.
Valsson et al. (1988) reported 6 affected persons in 3 Icelandic families which were remotely related. One of their patients, aged 17 years, showed no signs of muscular weakness despite easy fatigability. Morava et al. (2004) reported 2 sibs who had hypertrophic cardiomyopathy, infantile cataracts, and delayed motor development associated with lactic acidosis. One patient had intermittent 3-methylglutaconic aciduria. One had severe hypotonia, both had exercise intolerance, and both showed normal development in later childhood. Biochemical studies showed a defect in multiple mitochondrial oxidative enzymes and decreased levels of mitochondrial adenine nucleotide translocator-1 (ANT1) protein (SLC25A4; 103220) in muscle.
Di Rosa et al. (2006) reported 5 unrelated patients with infantile onset of hypertrophic cardiomyopathy, cataracts, and hypotonia, consistent with Sengers syndrome. All had increased 3-methylglutaconic aciduria and lactic acidosis. Three patients died before age 2 years, and the 2 surviving children showed mental retardation. The authors noted that the phenotype was more severe than usually reported in Sengers syndrome, and suggested a mitochondrial defect.
Calvo et al. (2012) reported a girl who presented at age 9 months with hypertrophic obstructive cardiomyopathy and cardiac failure associated with metabolic lactic acidosis. She later had generalized muscle weakness and delayed motor development with normal cognitive development. She had multiple episodes of cardiac failure in childhood, but the cardiomyopathy was not progressive. At age 11 years, she became wheelchair-bound due to muscle weakness. Other features included early-onset cataract and aphakic glaucoma. During high school, she showed some cognitive decline, and developed osteopenia and premature ovarian failure. Sudden death from cardiac arrest during a viral illness occurred at age 18 years. Skeletal muscle biopsy showed decreased cytochrome oxidase staining, lipid vacuoles, and subsarcolemmal accumulation of abnormally shaped mitochondria. A second unrelated infant, born of consanguineous Pakistani parents, developed respiratory distress and circulatory failure in the first hour of life, associated with severe metabolic lactic acidosis. Studies suggested persistent pulmonary hypertension. Other features included bilateral cataracts and thrombocytopenia. The patient died at age 3 days. Skeletal muscle biopsies of the 2 patients reported by Calvo et al. (2012) showed combined deficiencies of mitochondrial complexes I, III, and IV and severe mtDNA depletion (4% and 13% of normal, respectively).
Mayr et al. (2012) reported 5 patients, including 2 sibs, with Sengers syndrome and provided follow-up of 7 previously reported patients. Although all had congenital cataracts and hypertrophic cardiomyopathy, the phenotype was highly variable in terms of severity, survival, and biochemical alterations. Six of 12 patients had a combined deficiency of respiratory chain complexes in muscle, whereas 5 had normal results. Five patients died before age 12 months, whereas the oldest was alive at age 41 years. Most had muscle hypotonia, exercise intolerance, and lactic acidosis associated with exercise. The most severely affected patient was a boy who presented in the first weeks of life with congenital cataracts, hypotonia, decompensated massive cardiomyopathy, and tachydyspnea associated with increased serum lactate. He died of cardiac failure on day 18 of life. Muscle biopsy showed mild myopathic changes, fine lipid droplets, and a defect of complexes I, II, III, and V of the mitochondrial respiratory chain, as well as impaired ATP synthesis. A patient reported by Di Rosa et al. (2006) was 12 years old. Her cardiac condition was relatively stable under therapy, but her muscle weakness had progressively worsened, and she was wheelchair-bound for longer distances. She also had poor growth, but no sign of central nervous system involvement; brain MRI was normal. A younger brother, who had bilateral cataracts, had died at age 14 months as a result of hypertrophic cardiomyopathy. Muscle biopsy showed diffuse complex IV deficiency with numerous ragged-red fibers.
PathogenesisWhile several pieces of evidence pointed indirectly to the involvement of oxygen free radicals in the etiology of cardiomyopathy with cataracts, direct evidence was provided for the first time by Luo et al. (1997) who showed that complex I deficiency is associated with an excessive production of hydroxyl radicals and lipid peroxidation. Patients with isolated NADH:ubiquinone oxidoreductase (see 161015) deficiency (or complex I deficiency) most commonly present with fatal neonatal lactic acidosis or with Leigh disease (256000). Pitkanen et al. (1996) demonstrated 3 additional clinical phenotypes, cardiomyopathy with cataracts, hepatopathy and tubulopathy, and mild developmental delay.
Although the clinical features of Sengers syndrome suggest a mitochondrial disorder, no abnormalities are found on routine mitochondrial biochemical diagnostics, viz., the determination of pyruvate oxidation rates and enzyme measurements. In immunoblot analysis, Jordens et al. (2002) found that protein content of mitochondrial ANT1 was strongly reduced in the muscle tissues of 2 unrelated patients with Sengers syndrome. In addition, low residual ANT1 activity was detected upon the reconstitution of detergent-solubilized mitochondrial extracts from the patients' skeletal or heart muscle into liposomes. In 1 family, Jordens et al. (2002) found that a normal brother and an affected sister had the same ANT1 haplotypes in heterozygous form, which suggested that mutation in the ANT1 gene is not the primary cause of Sengers syndrome. In the aforementioned family, the disorder was thought to be recessive because of the occurrence of 3 affected sibs and consanguineous parents, 5 and 6 generations back, who were unaffected Valsson et al., 1988. Furthermore, Jordens et al. (2002) found no sequence abnormality or aberrant splicing of ANT1. Thus, they proposed that 'transcriptional, translational, or posttranslational events' are responsible for the ANT1 deficiency associated with Sengers syndrome.
Molecular GeneticsIn 2 unrelated patients with myopathic mtDNA depletion syndrome, Calvo et al. (2012) identified homozygous or compound heterozygous mutations in the AGK gene (610345.0001-610345.0003).
In 10 patients from 9 families with Sengers syndrome, Mayr et al. (2012) identified 12 different pathogenic mutations in the AGK gene (see, e.g., 610345.0004-610345.0009). The initial mutations were found by exome sequencing of an affected boy, born of unrelated parents of Italian descent. He had a severe phenotype, with death at age 18 days. Subsequent sequencing of this gene in 13 individuals with cataracts and cardiomyopathy revealed 12 pathogenic AGK alleles. Several of the patients had previously been reported by Lalive d'Epinay et al. (1986), Morava et al. (2004), and Di Rosa et al. (2006). The mutations were predicted to result in a loss of function.