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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #157: Monogenic Disorders of the Beta Cell Part 7

Dec 25, 2018

Maternally inherited diabetes and deafness (MIDD)

Maternally inherited diabetes and deafness (MIDD) most commonly results from heteroplasmic G to A substitution of the mitochondrial DNA at nucleotide pair 3243 in one of the two tRNA(Leu) genes [90].


The same mutation that causes MIDD (m.3243A>G) also causes a syndrome of severe neuromuscular disease called MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke). Within a family there is usually a dominant phenotype, although occasionally some members develop MIDD whilst others develop MELAS [91]. Most subjects with MELAS do not develop diabetes, although it has been described. It is not clear why some m.3243A>G carriers develop MIDD whereas others develop MELAS, but it would appear that they are two distinct but overlapping syndromes.

The prevalence of MIDD was 1.3% in a cross-sectional study of the diabetic population in the Netherlands [92]. All children of a mother with an m.3243A>G mutation will inherit the mutation, to some extent. However, only 60% of 3243 mutation carriers will develop diabetes, the remainder seem to have normal glycemic profiles during OGTT in middle age [92]. Spontaneous 3243 mutations have been described, so a lack of family history of diabetes or deafness does not exclude MIDD.

Phenotype of MIDD

Diabetes usually develops insidiously in the third to the fifth decade, although the age of presentation is variable, and a fifth of patients present acutely. Pancreatic autoantibodies are usually negative [93]. Over 75% of diabetic m.3243A>G mutation carriers have sensorineural deafness, though this may reflect diagnostic bias (i.e., testing those with diabetes and deafness) [91]. The deafness may present after the diabetes; however, it is usually present in other family members to raise suspicion of MIDD. Hearing loss is more common and more marked in men than women; it is usually loss of high-frequency perception and often requires use of a hearing aid [92] (see Table 28.4).Other features of MIDD reflect the overlap of this syndrome with MELAS. Neuromuscular signs especially myopathy, high serum lactate or lactate:pyruvate ratio, nephropathy, cardiac problems with ECG abnormalities, and spontaneous abortions are described [92,93]. Many patients with m.3243A>G mutations have pigmentary retinal dystrophy, although this does not usually affect vision. Patients withMIDDhave a high prevalence of renal disease leading to end-stage renal failure, although this can in part be attributed to diabetic nephropathy. The most common histologic finding is of focal segmental glomerular sclerosis, this can predate the diabetes or deafness.

Diagnosis of MIDD

The suspicion of MIDD should be raised in any family with diabetes, deafness, or other unusual neurologic features. Diagnosis is made by confirmation of a mitochondrial DNA defect at position 3243. Low heteroplasmy levels in blood can, however, mean that a mitochondrial mutation is missed. If clinical suspicion is high then the molecular diagnosis should be repeated on DNA from urine or oral mucosa, where the heteroplasmy rates are higher.

Treatment of MIDD

Most patients are treated with diet and oral agents at first although there tends to be a rapid progression to insulin, being started at a mean of 2 years after diagnosis. Metformin should probably be avoided because of the overlap with MELAS and risk of metformin precipitating lactic acidosis.

Coenzyme Q10 has been shown to improve respiratory chain function in mitochondria with the m.3243A>G mutation. Anecdotal case reports suggest coenzyme Q10 may prevent hearing loss and delay diabetes in MIDD without side effects, although they mostly just show some improvement in muscle function and lactic acid accumulation on exercise. Maintaining sufficient\ thiamine intake is thought to be important to optimize mitochondrial function.

Wolfram syndrome

Wolfram syndrome is also referred to as DIDMOAD due to the usual occurrence of Diabetes Insipidus, Diabetes Mellitus,Optic Atrophy, and Deafness, although only the presence of diabetes mellitus and bilateral progressive optic atrophy are necessary to make the diagnosis of Wolfram syndrome.The syndrome is rare, with a prevalence of 1.3 per million population in the UK [94].

Molecular genetics of Wolfram syndrome

Wolfram syndrome is an autosomal recessive disorder with consanguinity of patients’ parents being common. It is caused by mutation in the WFS1 gene or Wolframin in over 90% of patients [95] and rarely missense mutations in the CISD2 gene [96].

Clinical features of Wolfram syndrome

Two case series, comprising about 100 individuals with Wolfram syndrome have given a clear clinical phenotype [94,97]. Diabetes mellitus was the commonest presenting feature (diagnosis median age 6 yrs (range 3 weeks –16 yrs); 95%were treated with insulin at outset, and C-peptide was low or undetectable. Optic atrophy was diagnosed at a median age of 10 years (range 3–30 yrs) and progresses to blindness in most patients. Deafness was present in (46–62%) of patients.

Other features were less common and usually presented later: 50% have diabetes insipidus; 55% renal tract abnormalities (dilated renal outflow tracts and bladder atony); 55% neurologic abnormalities. Males frequently had primary gonadal atrophy and females had menstrual irregularity and delayed menarche but have conceived normal children [94]. There is a high mortality with a median age of death in the UK series of 30 years (range 25–49).The most common causes of death were respiratory failure or dysphagia due to brainstem involvement (see Table 28.4).

Diagnosis and treatment of Wolfram syndrome

The development of optic atrophy in a young person with insulin-treated diabetes mellitus should raise suspicion of Wolfram syndrome. Other clinical features should be sought and the diagnosis confirmed by molecular genetic analysis, with direct sequencing of the WFS1 gene. There is no treatment to alter outcome of the disease. Diabetes requires insulin treatment with other symptoms being treated as required.


In monogenic β-cell diabetes the importance of making a correct diagnosis has seen molecular genetic sequencing move rapidly from a research tool to clinical care.The use of diagnostic molecular genetics results in new challenges for the clinical diabetes team. Tests are expensive and need to be performed in the patients where monogenic diabetes is most likely. Genetic results need to be correctly reported and interpreted [98]. A molecular genetic diagnosis in a patient needs to be followed by appropriate treatment change and clinical follow-up and also appropriate testing (both biochemical and genetic) for family members.

This change in clinical practice needs to occur in a specialty where there has been very little training in genetics. A source of valuable information for doctors, nurses, and patients can be found at www.diabetesgenes.org.

All Chapter 28 references.