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Journal of Alzheimer’s Disease 40 (2014) 863–868 DOI 10.3233/JAD-131847 IOS Press
Short Communication
Yueqing Hu, Jingyao Liang and Shengyuan Yu∗
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High Prevalence of Diabetes Mellitus in a Five-Generation Chinese Family with Huntington’s Disease Department of Neurology, Chinese PLA General Hospital, Beijing, P.R. China
Accepted 27 December 2013
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Handling Associate Editor: Yong Shen
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Abstract. Huntington’s disease (HD) is associated with diabetes mellitus (DM) in population studies, but no case has been reported in a large HD family. We report a case of a five-generation Chinese family who is afflicted by both HD and DM. The prevalence of DM in HD of this family was high (72.7%). The diagnosis of HD in 11 family members was confirmed by the genetic test of the proband who had 42 CAG repeats. Furthermore, the proband’s daughter had abnormal locus at G3460T in MT-ND1 among mtDNA genome. Our case report suggests a genetic link between HD and DM.
INTRODUCTION
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Keywords: Diabetes mellitus, genes, Huntington disease, pathogenesis
Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by an abnormally expanded CAG repeat in the first exon of the huntingtin gene [1]. Individuals with more than 36 CAG repeats will manifest the symptoms of HD. Its severity is dictated by the length of the trinucleotide repeats [2, 3]. HD is one of several genetic syndromes found to be associated with diabetes [4]. In clinical studies, an increased incidence of diabetes mellitus (DM) has been reported in HD [5, 6]. However, pathological examination of the pancreatic tissue at different disease states of HD patients and mice showed that insulin levels were similar to that of the controls [7]. Moreover, there is no large family case report to sug∗ Correspondence to: Shengyuan Yu, PhD, MD, Department of Neurology, Chinese PLA General Hospital, Fuxing Road 28, Haidian District, Beijing 100853, P.R. China. Tel.: +86 10 55499118; Fax: +86 10 88626299; E-mail:
[email protected].
gest a genetic link between HD and DM. We report here a five-generation Chinese family manifested with symptoms of HD with autosomal dominant inheritance and with high prevalence of DM. CLINICAL DETAILS The proband, a 59-year-old woman, first noticed mild involuntary movement of her limbs at age 49. Her daily activities were not affected because these symptoms were mild at onset, so she had not sought medical care until she developed dysarthria, mood swings, and rapid, abrupt, and unintentional movements of her limbs, trunk, and neck. These abnormal movements were absent at sleep and were exacerbated by stress. She did not have a history of drug abuse or medication allergies. Examination revealed impaired cognition (Mini-Mental State Examination, 19/30), mild anxiety (Self-rating Anxiety Scale, 54/100), and depression (Self-rating Depression Scale, 58/100), hypomyotonia,
ISSN 1387-2877/14/$27.50 © 2014 – IOS Press and the authors. All rights reserved
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Fig. 1. A) Axial T1 and T2-weighted MRI of the proband revealed atrophy of the cerebral cortex, basal ganglia structures, and white matter. The ventricular system expanded as well. An arrow indicated the caudate nucleus. B) Capillary electrophoretogram of the proband showed forty-two CAG repeats, higher than the negative. C) Chromatogram of the variant G3460T in MT-ND1 among mtDNA for proband’s daughter was presented in the top right corner. The genetic defects were demonstrated by a black border. D) The pedigree of the five-generation Chinese family was showed at the bottom of the figure. The meaning of the symbols was attached in the left of the pedigree.
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Table 1 Demographics of the diabetic patients in the family Gender
Age at onset of DM
Duration of DM
Age at death
F F M M F F F M M F M F F
45 43 40 48 50 48 52 40 50 52 47 45 48
NA 7 9 7 8 7 2 5 2 4 6 3 6
NA 50 49 55 58 – – 45 52 – – 48 –
DNT, diabetic nutritional therapy; NA, not available.
Treatment for DM DNT and metformin DNT and metformin DNT, metformin, and insulin DNT, metformin, and insulin DNT, metformin, and insulin DNT, metformin, and insulin DNT and metformin DNT, metformin, and insulin DNT and metformin DNT and metformin DNT, metformin, and insulin DNT and metformin DNT and metformin
years [9]. Moreover, six HD patients died from injuries secondary to repeated falls and two from pulmonary infection. Deglutition barrier and psychosis might be other causes of death. Her parents did not have a history of HD (Fig. 1D). Her father died from cerebrovascular disease at the age of 50 years old, probably before the manifestation of HD symptoms. Her mother was 85 years old with normal neurological examination. This study was approved by the Ethics Committee of the Chinese PLA General Hospital, Beijing and consent was received by the family.
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and grade IV myodynamia in all extremities. Slitlamp examination was negative for Kayser-Fleischer ring in both eyes. Brain magnetic resonance imaging (MRI) revealed bilateral atrophy of the caudate nucleus and putamen with enlarged ventricles, consistent with HD (Fig. 1A). The laboratory tests did not show any evidence of Wilson’s disease, systemic lupus erythematosus, hyperthyroidism, or acanthocytosis. DNA analysis showed the presence of 42 CAG trinucleotide repeats on chromosome 4 in the proband and 17 CAG repeats in her daughter (Fig. 1B). The complete mtDNA sequence testing of the proband was normal. But the locus of G3460T on MT-ND1 of her daughter’s mtDNA was abnormal (Fig. 1C). It was identified as a candidate gene for Leber hereditary optic neuropathy (LHON) [8]. She had a strong family history of HD (Fig. 1D). We collected her family history by interviewing the living family members. For the deceased, the history was obtained by chart reviewing or interviewing of their first or second degree relatives. There were 30 members in this five-generation Chinese family. Among them 11 members suffered from HD (11/30), 13 type 2 (noninsulin-dependent) diabetes mellitus (T2DM, 13/30), and 8 both diseases (8/30). The prevalence of T2DM in HD patients was 72.7% (8/11). The demographics were shown in the Table 1. Insulin sensitizers, such as metformin, were used as first line treatment. Some of them failed to respond and were subsequently treated with insulin. However, no data was available to evidence whether anti-diabetic agents help or accelerate the symptoms of HD, which might be attributed to lack of neurology follow-up after the diabetes treatment. Additionally, nine HD patients died from age 43 to 58 years old, consistent with the average death age of Chinese HD patients which was 45.6 ± 13.5
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DISCUSSION We reported a HD pedigree of a five-generation family also affected with DM. This is the first Chinese family reported with this comorbidity. This pedigree showed that HD was a neurodegenerative disorder of autosomal dominant inheritance. Although abnormal carbohydrate metabolism has been documented in patients with HD [5], there was no study in the Chinese population. Several reasons may contribute to the dearth of study, including the low prevalence of HD and lack of recognition of the association between HD and DM. The prevalence of DM in this five-generation HD family was much higher than the estimated 3.9% (urban 5.2%, rural 2.9%) prevalence of diabetes in China in 2009 [10]. In our report, the brain MRI of the proband showed mild atrophy of the caudate nuclei with marked dilatation of the ventricles in the hypothalamus regions. In fact, impaired glucose metabolism is observed radiographically in the caudate nucleus of the asymptomatic subjects [11], prior to atrophy of this nucleus. The hypothalamus integrates signals of the energy level
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reduction in insulin mRNA [27]. Insulin exocytosis is reduced in R6/2 pancreatic -cells owing to a dramatic reduction in the number of intracellular secretory vesicles [31]. Mhtt was reported to disrupt intracellular transport and insulin secretion by direct interference with microtubular beta-tubulin [34]. Taken together, insulin dysfunction in HD is likely associated with mhtt. We did not find variation in the proband’s mtDNA genome, however, a mutant locus was detected at G3460T in MT-ND1 (subunit one of complex INADH dehydrogenase) gene among her daughter’s mtDNA, which was identified as one of candidate genes for LHON [35, 36]. Of note, maternally inherited LHON with infantile bilateral striatal neurosis patients manifest basal ganglia degeneration and associated movement disorders similar to those seen in HD patients [37]. Moreover, biochemical analysis of HD patients’ blood platelet and muscle mitochondria has revealed a Complex I defect [38, 39]. Subsequently, impaired mitochondrial function and increased oxidative stress are commonly observed in both diseases [40–42]. These similarities in the two diseases suggest that there may be a link between HD and LHON.
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from peripheral organs and is one of the main regulators of energy metabolism. Previous studies have shown atrophy and cell death of the hypothalamus in HD patients and animal models [12, 13]. This change also has been reported to associate with the alteration in endocrine function of HD, like high incidence of impaired glucose tolerance [5, 14], abnormalities of growth hormone (GH) [15–17] and disorder of cortisol levels [18–20]. GH of HD patients is raised to abnormally higher levels than the control subjects during the glucose tolerance test [14, 15]. Dysregulation of GH can contribute to some signs and symptoms in HD patients, which is possibly due to an imbalance among the biogenic amines involved in hypothalamic secretion of growth hormone-inhibiting factor and growth hormone-releasing factor [15, 21]. The increase in dopamine or serotonin activity could disrupt neurotransmission in the hypothalamus and lead to a rise in GH level. Furthermore, high GH could suppress the utilization of plasma glucose, subsequently leading to hyperglycemia. Thus hypothalamus dysfunction may play an important role in abnormal glucose metabolism of HD patients. Though we did not have data available to test whether the anti-diabetics agents helped or accelerated the symptoms of HD patients, the benefits from several hypoglycemic agents have been found in HD mice. Exendin-4 (an FDA-approved antidiabetic glucagon-like peptide 1 receptor agonist), metformin, glibenclamide, and insulin-like growth factor-1 might show efficacy in HD models, including: (i) improved glycemic control and normalized the insulin levels; (ii) suppressed brain and pancreatic pathologies; (iii) ameliorated motor function and extended survival; and (iv) decreased htt aggregate accumulation [22–25]. Prospective, placebo controlled studies are warranted to address the treatment for abnormal carbohydrate metabolism in patients with HD. Mutant htt (mhtt) was believed to impair neuron cell in cerebral cortex and striatum [26] and proved to be widely expressed in most tissues [27, 28], including the pancreas [28, 29]. The impairment of pancreatic islet cells may be involved in the development of glucose intolerance and insulin-deficient diabetes observed in HD patients and animal models. The pancreatic levels of insulin and insulin mRNA were reduced in R6/2 mice [27, 30]. Moreover, htt aggregates were latter identified to be expressed in -cells [31–33], which explained why -cells become dysfunctional in HD patients. The appearance of htt aggregates coincided with impaired mRNA expression of the key regulators of insulin gene expression and with a progressive
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CONCLUSIONS Our case report of a five-generation family of HD has shown high prevalence of DM, suggesting a genetic link between the two diseases. Further genome wide association studies are warranted to explore the underlying mechanism of this comorbidity. ACKNOWLEDGMENTS We would like to thank Dr. Yiming Mu (Department of Endocrinology, Chinese PLA General Hospital, Beijing, China) for reviewing the paper. Authors’ disclosures available online (http://www.jalz.com/disclosures/view.php?id=2085). REFERENCES [1]
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