A case of young diabetes and parasuicide

Abstract

Wolfram syndrome is a rare monogenic cause of juvenile onset diabetes mellitus. It is a non-autoimmune, insulin-deficient state with concurrent or consequent optic atrophy. Here we depict the case of a 16-year-old young girl afflicted with this condition, who presented with parasuicide on a background of depressive disorder. The aetiology of this presentation was attributable to multiple physical ailments and a genetic predisposition conferred by the disease-causing mutation for which she tested positive. She was managed with intensive insulin therapy and specific psychotherapy. Her case highlights the importance of recognising and addressing these comorbidities associated with Wolfram syndrome, so as to curtail disastrous consequences.

Background

Young or juvenile onset diabetes is a challenge for patients, their parents and physicians alike. The pertinent issues pertain not only to the diagnosis and treatment but also to long-term follow-up and management of comorbidities. The case presented here is a classic case of Wolfram syndrome(WFS) fulfilling the clinical criteria for diagnosis, further corroborated by genetic analysis. This young girl had multiple endocrinopathies including insulin-requiring diabetes mellitus, central diabetes insipidus and hypogonadotropic hypogonadism. She also had bilateral optic atrophy. Psychiatric comorbidities and suicidal ideation are not uncommon in young type 1 diabetes mellitus (T1DM) and are mostly due to insulin injections. However, both suicides and parasuicides are much more common in patients of Wolfram syndrome as a consequence of insulin injection and due to putative mechanisms involving the mutated gene in this condition. Amidst a background of several physical issues, the psychiatric comorbidities may receive less attention than they deserve. This poignant tale underlines the importance of early recognition and management of background depression and other possible psychiatric issues in such patients.

Case presentation

A 5-year-old girl, recently diagnosed with diabetes mellitus, had osmotic symptoms at presentation with insulin requirement from the beginning. However, she had poor glycaemic control. She later presented with painless, progressive diminution of vision which was diagnosed as bilateral optic atrophy without diabetic retinopathy. Intravenous pulse steroid therapy was prescribed for the same, resulting in only minimal improvement. Gradually, she developed reduced hearing ability which was due to sensorineural deafness. Her polyuria and polydipsia worsened despite reasonably controlled glycaemia, prompting a diagnosis of diabetes insipidus, needing desmopressin at around 9 years of age. She did not manifest signs of puberty till around 15 years which was the major concern of parents when she presented to us. On evaluation, she was found to have short stature (−2.5 SD), Tanner stage axillary hair+, pubic hair P2 and breast stage B1. Investigations revealed high glycaemic burden (glycated haemoglobin (HbA1c) was 9.2% or 77 mmol/mol, low gonadotropins (LH/FSH 0.8/1.5 IU/L), low estradiol (E2 5 pg/mL), normal thyroid functions, liver and renal function tests. Her basal cortisol and prolactin values were normal (410 nmol/L and 9.5 ng/mL, respectively). Contrast-enhanced MRI of the brain and sella was unremarkable as was ultrasonological examination of the abdomen. She was prescribed combined oral contraceptives which led to regular menstrual cycles, and she was lost to follow-up. At 16 years age, she attempted suicide by self-strangulation, and parents immediately sought medical attention again. Psychiatric evaluation revealed severe depression due to poor body image and the disease process. Her mother stated that she was overtly concerned about her poor vision, height and chronic nature of disease which had caused her to remain aloof for the past few months. Genetic analysis of the index patient revealed homozygous deletion c.1240_1242delTTC in the WFS gene, which is predicted to cause loss of a single amino acid residue (p.Phe414del) and is pathogenic in causing Wolfram syndrome. Both parents were also tested and their genetic analyses showed positive carrier status c.1240_1242delTTC (F414del). The father and daughter additionally showed c.1832A>G (R611H) rs734312 in father (heterozygous), and the patient (homozygous) which carries an increased risk for suicidal tendencies.

Investigations

HbA1c revealed uncontrolled glycaemic burden. Oestrogen was low with low gonadotropins suggestive of functional hypogonadotropic hypogonadism. High plasma and low urine osmolality was suggestive of central diabetes insipidus. Fundus showed bilateral primary optic atrophy without any changes of background retinopathy. MRI of the brain and sella was essentially normal. Genetic analysis from peripheral blood DNA sample revealed homozygous mutation causing deletion at a previously documented pathogenic locus on the WFS1 gene. Additional translocation was noted at a different gene locus, which confers an increased risk for suicidal tendencies.

Differential diagnosis

In a young patient presenting with insulin-requiring diabetes mellitus, T1DM and Wolfram syndrome are the initial possibilities while T2DM and pancreatogenous causes are less common. However, the presence of optic atrophy, negative autoantibodies and no diabetic ketoacidosis despite uncontrolled glycaemia, strongly rule in Wolfram syndrome and rule out T1DM. Additionally, diabetes insipidus and sensorineural deafness favour a diagnosis of the former over others, the acronym being diabetes insipidus, diabetes mellitus, optic atrophy and deafness (DIDMOAD). Mitochondrial diabetes is a differential to be considered in the background of diabetes and sensorineural deafness, however, the presentation is usually in the third to fourth decade.

Treatment

The patient was managed with intensive insulin therapy and specific psychotherapy during hospital stay and after discharge. She was also prescribed desmopressin and escitalopram.

Outcome and follow-up

At 6 months follow-up, patient was better with no repeat attempts of suicide but her glycaemic burden remained high due to non-compliance.

Discussion

Juvenile onset diabetes is a challenging issue with profound long-term implications. The spectrum of causes ranges from T1DM, MODY, pancreatogenous diabetes, mitochondrial aetiology to T2DM and Wolfram syndrome. Wolfram syndrome is a rare monogenic cause of juvenile diabetes. Epidemiology reveals its rarity with an estimated frequency of occurrence of 1 in 5 50 000 children.¹ One in every 150 patients with young onset, insulin-requiring diabetes mellitus is attributable to this syndrome. The acronym DIDMOAD includes the main clinical characteristics of the syndrome.

Wolfram first described diabetes mellitus and optic atrophy in four siblings out of eight, three of whom subsequently developed neurosensory hearing loss and two a neurogenic bladder.² Since then, the cases described in literature usually have a clinical profile of presentation as juvenile diabetes in the first decade of life which is insulin dependent but non-autoimmune. It differs from T1DM by presentation at an earlier age, lesser predisposition to diabetic ketoacidosis, more chances of hypoglycaemia as well as hypoglycaemia unawareness and usually negative autoantibody profile. The earlier age of presentation of diabetes could be due to the fact that endoplasmic reticulum (ER) stress is present since birth whereas the hallmark of T1DM that is, autoimmunity, can develop only after 6 months of age.

Clinical suspicion should be made in a young patient with non-autoimmune, insulin-requiring diabetes, with concurrent or subsequent primary optic atrophy. These are, in fact, the main criteria to be fulfilled for diagnosis.³ However, it is to be borne in mind that not all patients with juvenile onset diabetes mellitus and optic atrophy have this syndrome. Other differentials that warrant consideration include congenital rubella syndrome, hereditary optic neuropathy, Friedreich’s ataxia, Refsum’s syndrome, Laurence-Moon-Biedl syndrome and Alstrom syndrome. The diabetes insipidus that occurs as part of this syndrome is usually central, associated with structural and functional defects of the supraoptic and paraventricular nuclei of the hypothalamus. Sensorineural deafness can be seen due to dysfunction of cochlear neurons, vestibulocochlear nerve fibres, central nervous pathways in the brainstem or inferior colliculus. Other endocrinopathies that have been reported include gonadotropin, growth hormone and corticotropin deficiency.¹ Central nervous system can be involved with manifestations of ataxia, psychiatric disease, cognitive dysfunction or early neurodegeneration affecting both grey and white matter.⁴

The implicated gene is the WFS1 gene on chromosome 4p16.1 which encodes for an 890 amino acid protein wolframin, an integral glycoprotein in the ER. Mutation of this gene leads to accumulation of unfolded proteins including insulin, causing ER stress which can pre-empt cell apoptosis.⁵ Most mutations are located at exon 8 of the WFS1 gene⁶ which encodes the carboxy terminal extracellular part of wolframin at the luminal site of the ER membrane.⁷ Despite being ubiquitously expressed, differences between tissues with high (ie, pancreatic β-cells, brain, retinal amacrine or Muller cells) and with low (ie, blood or kidney) expression of the gene are quite significant. Again, in the pancreas, the gene is majorly expressed in β cells, less in δ cells and not found in α or exocrine cells. Thus, there is selective apoptosis of pancreatic β cells, neuroendocrine, neuronal and retinal cells, leading to a progressive endocrine dysfunction due to defects in insulin processing and secretion,⁸ neurodegeneration and optic atrophy. Genetic analysis of patients seems to be essential, if not mandatory, to precisely identify the monogenic cause in a patient of juvenile diabetes requiring insulin. It also holds importance in identifying asymptomatic carriers of the index patient. However, a genotype–phenotype correlation is not always feasible.

Apart from the physical ailment, addressing the psychiatric issues in these patients remains underemphasised. Research points to the fact that these comorbidities are more frequent in Wolfram syndrome than in T1DM. In patients with T1DM, insulin injections per se, number of injections and the chronicity of the disease contribute to increased depression, suicidal ideation and parasuicides (10%–20% prevalence).^{9 10} However, in Wolfram syndrome, the prevalence of depression is around 30% and that of parasuicides is around 25%.¹¹ Even, heterozygous carriers have been reported to carry a risk as high as 26 times that of the general population for depression and parasuicides.¹² The psychiatric comorbidities in this condition have been found to be intrinsic to the disease pathogenesis and not only a consequence of various associated impairments or insulin injections. The fact that there may be an underlying genetic predisposition to the same as part of this syndrome has been postulated.

In conclusion, our patient harboured a mutation variant that could underlie her extreme depression and suicidal tendencies, and this was inheritable as her father was found to be a carrier of the same variant. This aspect of the disease contributes to significant morbidity and mortality and needs to be part of the comprehensive management strategy.

Learning points.

• Vision loss in a patient of insulin-requiring diabetes mellitus without diabetic retinopathy should suggest a diagnosis of Wolfram syndrome.

• Persistence of polyuria despite good glycaemic control indicates underlying diabetes insipidus.

• Suicidal ideation is not uncommon in young diabetes, but some variants of Wolfram syndrome are highly predisposed to it.