HYPERGONADOTROPIC HYPOGONADISM, PROGRESSIVE EARLY-ONSET SPINOCEREBELLAR ATAXIA, AND LATE-ONSET SENSORINEURAL HEARING LOSS: CASE REPORT AND LITERATURE REVIEW
Sarikaya E,1 Ensert CG,2 Gulerman HC1
*Corresponding Author: Esma Sarikaya, Centre for Reproductive Medicine, Zekai Tahir Burak Women’s Health Research and Education Hospital, Talatpasa Bulvari Hamamonu 06230, Ankara, Turkey; Tel.: +90-312- 310-3100; Fax: +90-312-312-4931; E-mail: sudesarikaya@hotmail.com
page: 77

DIFFERENTIAL DIAGNOSIS

Phenotypic overlap and inter familial variability make the hereditary ataxias a notoriously difficult group of disorders to classify. New gene loci, which are linked to SCAs, are discovered every other day. Endocrine dysfunction is a common clinical feature in these patients, with hypogonadism occurring in approximately 5% [26]. The same problem is also present for SNHL, which is a component of more than 400 syndromes, and, so far, more than 30 genes associated with syndromic hearing loss have been identified. To date, more than 70 loci have been reported for non syndromic deafness, including approximately 40 autosomal dominant, 30 autosomal recessive, and eight Xlinked, and approximately 30 genes have been cloned. Mutations in GJB2, the gene that encodes the connexin 26 protein, are the most common cause of recessive deafness in the United States, and dominant low-frequency SNHL is most commonly caused by mutations in the Wolfram’s syndrome 1 gene. Usher syndrome is the most frequent cause of combined deafness and blindness in the industrialized world [27]. Association of ataxia and hypergonadotropic hypogonadism and hearing loss is extremely rare and part of well described autosomal recessive syndromes other than PS [6-9] (Table 1). Other syndromes that exhibit two or more signs of AAHH are: trinucleotide repeats disorders; fragile X syndrome (CGG repeat), Friedreich’s ataxia (GAA repeat) and five SCAs (1, 2, 3, 6 and 7) (CAG repeat), myotonic dystrophy (DM/ Curschmann-Steinert disease), proximal myotonic myopathy (PROMM or Ricker’s syndrome) (CTG repeats) [28], ciliopathies; Alström syndrome, Bardet- Biedl syndrome [29], the neurodegenerative mitochondriopathies; Huntington’s disease, Charcot-Marie- Tooth (CMT), Leber’s hereditary optic neuropathy, Kearns-Sayre syndrome (KSS), maternally inherited Leigh syndrome (MILS), and the neuropathy, ataxia, and retinitis pigmentosa (NARP) syndrome and other mitochondriopathies; Wolfram’s syndrome [30], muscle lipid diseases; lipid storage myopathy (LSM), multiple acyl-CoA dehydrogenase deficiency, glutaric aciduria type II, and neutral lipid storage disease with myopathy, β-oxidation cycle defects and deficiencies of carnitine palmitoyltransferase II (CPTH) and very long chain acyl-CoA dehydrogenase (VLCAD) [31]. Refsum’s disease (phytanic acid storage disease), and Zellweger syndrome (cerebro-hepato-renal syndrome), Uscher, Alport, Cockayne, Flynn-Aird, Hurler (MPS-1), Kearns-Sayre (CPEO), Norrie, 4H (hypomyelination with hypogonadotropic hypogonadism and hypodontia), Sohval-Soffer, Crandall, Woodhouse- Sakati, Marinesco-Sjögren’s, CAPOS syndromes, galactosemia and hereditary motor sensory neuropathies (HSMN)[16,23,33-38]. In a few reports, several moleculer analyses have been made for the differential diagnosis of these patients: Pierce et al. [5] applied whole-exome sequencing to identify the gene responsible for PS and found mutations in 17β-hydroxysteroid dehydrogenase type 4 [also known as D-bifunctional protein (HSD17B4/ DBP)], which is also detected in Zellweger syndrome [23]. They have also found mutations in mitochondrial histidyl tRNA synthetase HARS2 [38]. Nishi et al. [10] found no evidence of mitochondrial disease on a muscle biopsy, including respiratory enzyme assays; no ragged red fibers were found on muscle biopsy and there was only mild type IIB atrophy, a non specifc finding in many types of upper motor neuron lesions. In the evaluation by Fiumara et al. [16] none of the known mitochondrial or CMT mutations were present in the DNA of patient 1. Muscle biopsy showed atrophy with fat replacement. They also performed sural nerve biopsy in one patient (SM) and found severe loss of myelinated fibers with segmental demyelination and remyelination and scattered axonal degeneration suggestive of a form of hereditary motor sensory neuropathy (HSMN). Mitochondrial testing on patient 1 (LK) for MELAS 3243, SNHL-1555 and -7445 also did not show any of the mutations known to cause the mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes or some form of SNHL [16]. Marlin et al. [19] sequenced the whole mitochondrial genome, GJB2 (the most frequent form of isolated hearing impairment), AOA1, POLG, FRDA, (genes implicated in ataxia or ophthalmoplegia) and FOXL2 (a gene responsible for a premature ovarian failure), and did not find any mutation in patient 2. In one female with this association, partial deficiency of the mitochondrial enzyme cytochrome c oxidase was demonstrated by De Michele et al. [12]. Gironi et al. [39] reported two brothers who had late-onset progressive ataxia and hypergonadotropic hypogonadism associated with muscle CoQ10 deficiency. Before starting further laboratory investigations, we think clinical and neurological examinations must be fully performed in such cases. Long-term follow up is very important in these patients since some clinical manifestations appear later in life. It is also important to collect details on the general health, hearing, menstrual history and to report the presence of morphologic abnormalities of the ear, eye, face, or other organ systems, mental retardation, ataxia, epilepsy, Parkinson’s disease, autism of the relatives from both parental lines. It is also relevant to check for consanguinity and family ethnic background. This simple approach will provide the opportunity to recognize associated syndromes and evidence of the basis behind the initiation of further laboratory investigations. The assessment of a patient with AAHH requires a multidisciplinary approach and must include advice and support to the parents, and genetic counseling aimed at optimizing the use of the most adequate clinical resources. The laboratory tests must be confirmed according to clinical suspicion. Before making costly molecular analyses, simple blood tests for glucose, vitamin E, folate and B12 levels, α-fetoprotein, very long chain fatty acids and phytanic acid, lysosomal enzymes, amino and organic acids serum ammonia, arterial pH levels, and X-rays of the skeleton should be done. Performing ECG, muscle biopsy, measurement of mitochondrial enzyme cytochrome c oxidase and muscular CoQ10 levels and DNA analysis for trinucleotide expansions at the SCA 1, 2, 3, 6, 7 and Friedreich’s ataxia loci, and looking for mutations in HSD17B4 for a number of similar cases will give valuable information about the pathogenesis and differential diagnosis of this association. The late-onset of SNHL in many reported cases underlines the need for careful examination of acoustic acuity in cases of cerebellar ataxia and hypogonadism. The audiograms are also important to guide patient rehabilitation. The pathogenetic mechanism of AAHH is not yet fully understood. Considerable heterogeneity exists in the literature on the neurological manifestations, onset age, progression of symptoms, clinical severity and presence of associated abnormalities such as mental retardation (PS, Richards-Rundle syndrome) [5,11-15,19], epilepsy (mitochondriopathies) [12,14], nystagmus [3,10,12,19, present study], cataract, optic atrophy, retinal dystrophy or blindness (Alström and Wolfram’s syndrome, mitochondriopathies) [14,15], and endocrine anomalies (Wolfram’s, Alström, Richards- Rundle syndromes, mitochondriopathies) [10], short stature (Alström syndrome) [5,10], cardiac anomalies (PS and mitochondriopathies) in this association. This heterogeneity may be reflecting different degrees of severity within the entity of ovarian dysgenesis and neurological impairment and favors the hypothesis that AAHH is a heterogeneous syndrome. It is therefore very unlikely that cerebellar ataxia and hypogonadism are linked to a common genetic defect. As the physiopathology of PS is still unknown, the question remains whether one gene is implicated in all the different clinical forms of PS (with and without neurological symptoms) or if there are at least two different genes responsible for two different clinical entities. It is more reasonable to ascribe this association as a clinical entity with a different, yet not fully understood, pathogenetic mechanism in which the involvement of different genotypes may lead to the same or similar phenotypic manifestations. Association of ataxia hypergonadotropic hypogonadism and hearing loss could be caused by both a malfunction of the mitochondria and of myelination. Depending on the genes involved, it may have autosomal recessive or mitochondrial inheritance. The inter familial variation of both the severity of hearing loss and the onset of amenorrhea, and neurological symptoms in individuals with AAHH may turn out to be due to environmental or genetic factors influencing the effect of mutations. Proposed Causative Pathogenic Mechanisms Were as Follows: 1) Polymorphisms within the mitochondrial genome might lead to impaired energy generation and to an increased amount of reactive oxygen species, having susceptibility in several diseases. Mitochondria produce most of the cell’s supply of adenosine triphosphate (ATP), by means of the oxidative phosphorylation machinery, which comprises electron transport chain (ETC) and ATP synthase. The ETC dysfunction leads to reduced ATP production, impaired calcium buffering and increased generation of reactive oxygen species (ROS). Mitochondria have their own DNA; the mitochondrial DNA (mtDNA) carries 37 genes: 22 encoding for mitochondrial transfer RNAs (tRNAs) (for the 20 standard amino acids, plus an extra gene for leucine and serine), two for ribosomal RNAs (rRNAs) and 13 encoding for polypeptides subunits of complexes of the respiratory chain system, seven of these belong to complex I or NADH dehydrogenase (ND1, ND2, ND3, ND4, ND4L, ND5, ND6), one to complex III or cytochrome c reductase, three to complex IV or cytochrome c oxidase (COX I, COX II and COX III) and two to complex V or ATP synthase (ATPase6 and ATPase8). Increased production of ROS damages cell membranes and further accelerates the high mutation rate of mtDNA. Mitochondrial genetics differs from Mendelian genetics in three major aspects: maternal inheritance, heteroplasmy and mitotic segregation. Mitochondria are inherited in humans via the female line, transmitted as a non recombining unit by maternal inheritance [40]. There is significant evidence that the pathogenesis of several neurodegenerative diseases, including Parkinson’s disease, Alzheimer’s disease, Friedreich’s ataxia, multiple sclerosis and amyotrophic lateral sclerosis, may involve the generation of reactive oxygen species and/or reactive nitrogen species associated with mitochondrial dysfunction [40]. Leipnitz et al. [41] reported that oxidative stress is elicited in vitro by phytanic acid (Phyt) that accumulates in Refsum disease and other peroxisomal diseases. Phytanic acid increased thiobarbituric acid-reactive substances (TBA-RS) levels, carbonyl content and sulfhydryl oxidation, and decreased concentrations of glutathione (GSH). This effect was prevented by the antioxidants α-tocopherol and melatonin, suggesting the involvement of free radicals [41]. In one female with this association, partial deficiency of the mitochondrial enzyme cytochrome c oxidase was demonstrated by De Michele et al. [12]. Primary MCPs are either due to sporadic or inherited mutations in nuclear or mitochondrial DNA located genes. The MCPs should be considered in any patient with unexplained progressive multi system disorder in addition to AAHH [9]. 2) It can be related to the defect of a gene producing a protein or other product that affects both granulosa cells, neurons and hearing function. Proteins mentioned in the literature were wolframin, usherin, myosin, harmonin, cadherin 23, protocadherin 15, SANS, whirlin, VLGR1b Clarin-1, D-bifunctional protein (DBP) GPR98 proteins, connexin 26, neuronal proteins, mitochondrial protein, protein zero, norrin, huntington, frataxin, MKS1 and meckelin. In fragile X-associated tremor/ataxia syndrome (FXTAS), which is one of the most common singlegene forms of gait ataxia and tremor in older males; pre mutation in FMR1 causes the gene to make abnormally increased amounts of messenger RNA. This can be toxic to certain brain cells. A similar toxic mechanism might impair ovarian function and lead to hypergonadotropic hypogonadism [42]. Mutations in the SIL1 gene on chromosome 5q31 cause Marinesco- Sjögren’s syndrome and the loss of SIL1 function results in accumulation of unfolded proteins that are harmful to the cell [43]. Mutations in the GALE genes on chromosome 1p36-p35, GALK1 genes on chromosome 17q24, and GALT genes on chromosome 9p13 cause galactosemia. In galactosemia, hypergonadotropic hypogonadism may be due to toxic effect of galactose or its metabolites to the ovarian parenchyma [44]. Friedreich’s ataxia and Huntington’s disease are classified in the neurodegenerative mitochondriopathies and trinucleotide repeat disorders. Friedreich’s ataxia is caused by a GAA repeat expansion and mutations in the FXN gene on chromosome 9 that encodes frataxin. Frataxin is a mitochondrially targeted protein that is an iron chaperone and plays a role in mitochondrial iron handling which requires ETC constituents [45,46]. Huntington’s disease is caused by a CAG repeat expansion in one copy of the Huntingtin gene on chromosome 4, which encodes a protein called huntingtin that has been shown to physically associate with mitochondrial membranes and interfere with mitochondrial calcium handling. Huntingtin has been proposed to interfere with mitochondrial biogenesis by disrupting peroxisome proliferator activated receptor γ coactivator 1 α (PGC-1a), a transcription co-activator that facilitates mitochondrial biogenesis [47,48]. A mutation in the NDP gene causes Norrie disease. This gene encodes a secreted protein with a cysteinknot motif that activates the Wnt/β-catenin pathway. The protein forms disulfide-linked oligomers in the extracellular matrix. For the normal development of the eye and other body systems, norrin is believed to be crucial. Norrin also appears to be crucial in the specialization of the cells of the retina and the establishment of a blood supply to the inner ear and the tissues of the retina [49]. Mutations in HSD17B4 type 4 leads to a fatal form of Zellweger syndrome and may be PS [5,23]. Dbifunctional protein (DBP) and multifunctional protein 2 (MFP-2) encoded by HSD17B4, is a multi functional peroxisomal enzyme involved in fatty acid β-oxidation and steroid metabolism [5,23]. The WFS1 or wolframin gene provides instructions for making the wolframin protein which is located in the endoplasmic reticulum. More than 30 WFS1 mutations have been identified in individuals with a form of non syndromic deafness called DFNA6. Researchers have identified more than 100 WFS1 mutations that cause Wolfram syndrome. Some mutations delete or insert DNA from the WFS1 gene. As a result, little or no wolframin is present in cells. Other mutations replace one of the amino acids used to make wolframin. These mutations appear to reduce wolframin activity dramatically [50]. The USH2A gene encodes usherin protein and possesses laminin epidermal growth factor as well as fibronectin type III domains. Laminins are the major non collagenous components of basement membranes that mediate cell adhesion, growth, migration and differentiation. The discovery of three putative missense mutations (C319Y, N346H and C419F) in the laminin type VI domain of this protein mark this region for a potentially significant functional role in the cochlea and retina. Netrins are small diffusable proteins that control guidance of central nervous system commissural axons at the midline and peripheral motor axons. A homolog of netrin in C. elegans, UNC-6, is one of the cues in the extracellular matrix that guides dorsoventral migrations of pioneer axons and migrating cells along the body wall on the epidermis [51]. Mutations in 35delG, GJB2, the gene that encodes the connexin 26 protein a gap junction protein that is assumed to be a component of the potassium recycling pathway in the inner ear, are the most common cause of recessive deafness in the United States. To date, 48 recessive and seven dominant disease-causing GJB2 mutations have been identified in the 35delG allele, and is particularly common in Caucasian populations [52]. Charcot-Marie-Tooth disease (when associated with essential tremor and ataxia, called Roussy-Levy syndrome), which is the most common inherited neurological disorder, is caused by mutations that cause defects in neuronal proteins. The most common cause of CMT (70-80% of cases) is the duplication of a large region in chromosome 17p12 that includes the gene PMP22. Some mutations affect the gene MFN2, which codes for a mitochondrial protein [53]. 3) An inherited unstable trinucleotide repeat disorder, which is caused by an expansion of repetitive three bases in the causative gene, likely shares a common pathogenesis caused by the gain of a toxic function of the expanded polyglutamine tract and neurodegeneration. Fragile X syndrome (CGG repeat), Friedreich’s ataxia (GAA repeat) and five SCAs (1, 2, 3, 6 and 7) (CAG repeat), myotonic dystrophy (DM/ Curschmann-Steinert disease), proximal myotonic myopathy (PROMM or Ricker’s syndrome) (CTG repeats) Huntington’s disease (CAG repeat), major psychosis [28,54]. Recent findings in genetic research have suggested that a large number of genetic disorders, both genetic syndromes and genetic diseases, that were not previously identified in the medical literature as related, may, in fact be related in the gene-typical root cause of the widely-varying, phenotypically-observed disorders. Mutations in HSD17B4 (also known as D-bifunctional protein), which leads to a fatal form of Zellweger syndrome, have recently also been proposed as the first identified genetic cause of PS by Pierce et al. [5] and de Launoit et al. [23]. Alström syndrome is a ciliopathy [29]. Other known ciliopathies include primary ciliary dyskinesia, Bardet-Biedl syndrome, polycystic kidney and liver disease, nephronophthisis, Meckel-Gruber syndrome and some forms of retinal degeneration [55]. Gempel et al. [25] reported that the electron transferring flavoprotein dehydrogenase (ETFDH) gene, previously shown to result in another metabolic disorder, glutaric aciduria type II (GAII), leads to a secondary CoQ10 deficiency. Their results indicated that the late-onset form of GAII and the myopathic form of CoQ10 deficiency are allelic diseases. Aguglia et al. [56], described two brothers with Marinesco-Sjögren’s syndrome, both of whom also had very low serum vitamin E concentrations with an absence of postprandial chylomicrons. Findings on electron microscopy of the intestinal mucosa were consistent with a chylomicron retention disease. They also suggested that both chylomicron retention disease and Marinesco-Sjögren’s syndrome are related to defects in a gene crucial for the assembly or secretion of the chylomicron particles, leading to very low serum levels of vitamin E.



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