Long term follow-up in two siblings with Sengers syndrome: Case report

Sengers syndrome (SS, OMIM #212,350), is a rare autosomal recessive disorder described in 1975 with a prevalence < 1/1,000,000 [1]. It is clinically characterized by congenital cataract, hypertrophic cardiomyopathy, mitochondrial myopathy, and lactic acidosis, and genetically by mutations in the acylglycerol kinase (AGK) gene [2]. AGK codes for a mitochondrial protein, also known as multi-substrate lipid kinase (MULK), located in the inner mitochondrial membrane, and involved in the conversion of monoacylglycerol (MAG) and diacylglycerol (DAG) to lysophosphatidic acid (LPA) and phosphatidic acid (PA), respectively [3]. Independently of its lipid kinase activity, AGK is also required for the import and assembly of mitochondrial carrier proteins in the inner membrane [4], thus indicating that pathogenic mechanisms for SS rely both on defective lipid metabolism [2] and protein biogenesis in mitochondria [4].

Clinical course ranges from a severe fatal form, leading to death within the third year of age in around 86% of cases [8], to a more benign form with survival into adulthood [7], to an isolated form of congenital cataract [9]. To date, only 2/44 genetically reported patients [2‐23] have survived the second decade at their latest examination [10, 11], and no natural history data are available for the disease.

We present a long term follow up in two siblings affected by a slowly progressive benign form of SS. The association of congenital cataract, lactic acidosis, mitochondrial myopathy, and a mild hypertrophic cardiomyopathy suggested the diagnosis which was confirmed by the identification of pathogenic mutations in AGK gene, which codes for a protein involved in lipid metabolism and protein biogenesis in mitochondria. Consistently, muscle biopsy highlighted mitochondrial abnormalities, associated with impaired Complex I and IV activities in muscle homogenate, in accordance with previous reports [6, 7, 12].

We have been monitoring the cardiological evolution of both sisters for 20 years, with ECG, echocardiography, Holter monitoring and cardiac MRI, providing evidence of a mild stable form of hypertrophic cardiomyopathy without outflow obstruction and absence of arrhythmic events, not requiring pharmacological intervention, thus far. We underline the significant discrepancy between pronounced abnormality and severity of electrical features on ECG and the effective grade of ventricular hypertrophy documented by both echo and cardiac MRI. The severity of cardiomyopathy is the main clinical predictor of disease progression in SS. Indeed, the detection of outflow obstruction at diagnosis is usually associated with the severe form of the syndrome, and its development during the clinical course worsens the outcome in the milder form [11]. The absence of outflow obstruction, and the overall conserved cardiac function in our patients, suggested a mild form of SS.

In both cases, brain MRI failed to detect major cerebral, cerebellar, and brainstem abnormalities, revealing only mild hypoplasia of the inferior cerebellar vermis and anterior commissure in both siblings. Moreover, the white matter myelination was adequate for the age and MRS showed normal metabolic profiles. Of note, thinning of the optic nerves and chiasm was a consequence of the longstanding ocular problems. Neuroradiological examinations have been showed in around 30% of reported cases [1, 6, 16, 17, 19, 24], with the most common findings represented by hypoplasia of both the brainstem and inferior cerebellar vermis, impaired myelination of the cerebral hemispheres and brainstem, and cortical infarction. It has been suggested that the presence of radiological alterations might discriminate the severe form from the mild one [24]. Recent studies and our findings support this hypothesis, showing grossly normal brain MRI in mild form of SS [2, 17, 19, present study].

Our patients also presented a motor development delay in their infancy and a moderate to severe cognitive delay. While the first has been reported in 22 out of 23 patients [20], conversely, cognitive delay is rarely reported [14, 17] and its burden on the daily life of those who survive until the adult age is not known and should be studied in further studies. The milder cognitive impairment in the younger sister might be explained with an earlier diagnosis and initiation of a multidisciplinary rehabilitation program compared to her sister.

Both our patients presented with hypergonadotrophic hypogonadism related to ovarian agenesis, a disorder which has not been previously reported in SS, though premature ovarian failure was reported in a single case [15]. Since peripheral and central hypogonadisms are common in several mitochondrial diseases [25], and AGK is expressed in the ovarian and testis tissue [The Human Protein Atlas; available from: https://​www.​proteinatlas.​org/​ENSG00000006530-AGK/​tissue], the prevalence of hypogonadism might be underestimate in SS, suggesting that a work-up for an early recognition and treatment of this condition should be performed in those patients who survive the first decade.

A clear-cut genotype-phenotype correlation for SS has not been clearly defined yet, probably due to the few cases so far reported. However, a more severe phenotypes have been described in homozygous or compound heterozygous carriers of nonsense variants [8], whether all patients who survived the first decade, retained at least one splice site variant [7, 9]. Our patients harbored a homozygous splicing variant on the AGK gene, already described in compound heterozygosity with the nonsense c.1213 C > T/ p.Gln405* (see case 62,218 in [2]). The previously reported child displayed failure to thrive, progressive muscle weakness requiring wheelchair for distances longer than 100 m from 12 years on, and a cardiac condition treated with propranolol and idebenone. Our cases confirm that splicing variants are associated to milder forms, in particular when in homozygous state. However, genotype-phenotype relationships in SS remain loose. Indeed, two homozygous carriers of the c.424-1G > A splicing variant died at 10 days and 4 months, because of severe heart dysfunction [7], and an infant harboring the homozygous c.518 + 1G > A [22] died soon after birth for congestive heart failure.

In conclusion, we defined for the first-time the natural history of Sanger Syndrome in two siblings with a mild form of SS, across a 20-years follow-up. During this period, the patients showed an extremely slowly evolutive hypertrophic cardiomyopathy, a mild and stable myopathy associated to cognitive delay, and a condition of ovarian agenesis, not previously reported. We emphasize the importance of natural history studies on SS necessary to future clinical trial readiness.