Camptocormia and Other Orthopedic Compromise Dominating Mitochondrial Disorder: A Case Report

Objectives: Camptocormia and other orthopedic abnormalities have been only rarely reported as a phenotypic manifestation of a mitochondrial disorder (MID). Here we present an MID patient with multiple orthopedic abnormalities dominating the phenotype. Case report: The patient is a 55-year-old male in whom MID was diagnosed at age 34 upon clinical presentation, muscle biopsy, and biochemical investigations. Phenotypically, he manifested with multisystem disease including the brain (mental retardation, epilepsy, sleep disorder, cerebellar atrophy), eyes (cataract, myopia), ears (hypoacusis), heart (hypertrophic, cardiomyopathy, QT-prolongation, left anterior hemiblock, noncompaction), intestines (hepatopathy, cholecystolithiasis), muscle (myopathy), peripheral nerves (neuropathy), and the bone marrow (anemia). Additionally, there was facial dysmorphism (upslanting palpebral fissures, hypertelorism, protruding bulbs) and multiple orthopedic abnormalities, including camptocormia in the absence of axial myopathy, barrel thorax, gibbus, genu valga, knee contractures, bilateral gonarthrosis, bilateral ankle arthroses, and outwardly rotated feet. These abnormalities were complicated by wedge vortex, vertebral stenosis, and coxarthrosis requiring right hip endoprosthesis. His mother manifested with a largely different phenotype. Conclusions: An MID can manifest phenotypically with orthopedic abnormalities, which may dominate the phenotype. According to this case, orthopedic abnormalities in a MID can be unrelated to the severity of myopathy and intrafamilial phenotypic variability can be high in a MID.


Introduction
It is well established that mitochondrial disorders (MIDs) are frequently multisystem disorders [1] and that the phenotype of a maternally transmitted MID may vary considerably within a family and between families [2]. Orthopedic abnormalities, in particular camptocormia (bent spine syndrome), have been only rarely reported as a phenotypic manifestation of a MID [3]. Here we report an MID patient with predominant orthopedic involvement and high intrafamilial phenotypic variability.

Case Presentation
The index patient is a 55-year-old Caucasian male, height 160cm, weight 72kg, with a multisystem MID diagnosed upon clinical presentation, immune-histo-chemical, and biochemical investigations of a muscle biopsy at age 34. His history was noteworthy for mental retardation, epilepsy since age 12, cataract surgery, hypoacusis, vitamin D deficiency, hypertrophic cardiomyopathy (hCMP), left ventricular hypertrabeculation (LVHT)/noncompaction (Figure 1), QT-prolongation (Figure 2), left anterior hemiblock (LAH), anemia, cholecystolithiasis, sleep disorder, hepatopathy, hyperlipidemia, benzodiazepine misuse, myopathy, prostate hyperplasia, right total hip endoprosthesis, and iron deficiency ( Table 1). Since at least age 47 camptocormia became apparent. At age 48 he experienced a deep venous thrombosis after left tibial fracture. At age 51 he had undergone surgery for right-sided scrotal hernia. Seizures were well controlled with a seizure frequency of about two generalised tonic-clonic seizures per year and several focal seizures.    The 78-year-old mother of the index patient had a history of arterial hypertension, diabetes, hyperlipidemia, polyarthralgias due to polyarthrosis, deep venous thrombosis, recurrent leg edema, phlebitis, hyperuricemia, and listhesis L3/4. She had surgery of the right shoulder after a trauma, cataract surgery bilaterally, surgery for carpal tunnel syndrome bilaterally, and veins tripping four times. She refrained from being investigated neurologically during years despite frequently accompanying her son to his regular neurological visits. At the age of 74 she sought neurological advice for the first time after nerve conduction studies, carried out for sensory disturbances of the feet, had revealed sensori-motor polyneuropathy.
The index patient is noteworthy for the orthopedic abnormalities described above which have not been reported in combination. Orthopedic abnormalities previously reported in MID include scoliosis [4], genu valga [5], gibbus [6], pectus carinatum (pigeon breast) [7], brachydactylia [8], foot deformities [9], skeletal dysplasia [10], Kniest dysplasia [11], and camptocormia ( Table 2) [3]. Inwardly rotated feet and barrel thorax have not been reported in MIDs. Camptocormia has been only rarely reported in MIDs ( Table 2), most frequently in association with axial myopathy [12]. Affection of the axial muscles in the index case was not clinically evident but may have been present subclinically. Most likely camptocormia in the index patient was thus also due to subclinical weakness of the axial muscles.  Whether orthopaedic abnormalities in the index case were primary or secondary, remains speculative. Since there was no clinical evidence for weakness of the axial musculature and only mild weakness for foot extension, being attributed to polyneuropathy, we interpreted most of them as primary. Primary orthopedic disease may pathogenetically derive from abnormal embryonic development of the bones or cartilage. An explanation for the orthopaedic abnormalities in MIDs could be involvement of the hypoxic tissue cartilage in the metabolic breakdown [18]. Since skeletal growth is driven by expansion of cartilage in the growth plate [18], it is conceivable that disturbed cartilage proliferation may lead to orthopedic compromise during intrauterine or childhood development. Whether some of the orthopedic abnormalities (genu valga, gibbus) were attributable to vitamin D deficiency remains speculative, since it was well substituted during the last years. Whether the barrel thorax was due to cardiac involvement remains speculative but is rather unlikely given the high number of MID patients with cardiac involvement but without this thorax deformity described in the literature. Facial dysmorphism is a common finding in MIDs, which has been previously reported [11,19]. Most of the other phenotypic features are common in MIDs, except for camptocormia, which has been reported only in POLG1 mutation carriers.
Though not genetically confirmed, maternal transmission of the MID in the presented family is quite likely. Arguments for maternal transmission are that the mother had developed features of a MID, that mitochondrial DNA (mtDNA)-related MIDs are transmitted via the maternal line in 75% of the cases. and that none of the males in this family had transmitted the disease. The variable phenotype between mother and son does not exclude maternal transmission, as intrafamilial phenotypic variability in MID families can be high [2,20].
In conclusion this case shows that a MID can manifest phenotypically with orthopedic abnormalities, which may dominate the phenotype of a maternally transmitted MID. According to this case, orthopedic disease in a MID can be unrelated to the severity of myopathy and intrafamilial phenotypic variability can be high in a MID.

Conclusions
This case shows that a MID can manifest phenotypically with orthopedic abnormalities, which may dominate the phenotype of a maternally transmitted MID. According to this, orthopedic disease in a MID can be unrelated to the severity of myopathy and intrafamilial phenotypic variability can be high in a MID.

Additional Information Disclosures
Human subjects: Consent was obtained by all participants in this study. Neurol. Hospital rosenhügel issued approval not applicable. The patient gave written consent for all invasive investigations. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.