CME INDIA Case Presentation by Dr. Prabhat Agrawal, MD, FRCP (Edinburgh, Glasgow) FICP, FACP, Professor of Medicine, S. N. Medical College, Agra.

CME INDIA Case Study

What is this?

  • Presented to OPD.
  • He has history of GTCS for last 8-9 yrs.
  • Also, there is history of sudden episodes of hearing loss and vision loss.
  • He had one sister, also diabetic expired one year ago due to diabetes.
  • His mother also had diabetes, expired at the age of 23 year due to some complication.
  • His both mama (maternal uncle) have diabetes and hearing problems.
  • Mossi (Aunt) had no diabetes, expired due to some post-delivery compilation.
  • One mama (maternal uncle) also expired.

Family Tree as traced by staff

Unique Case of A 25-Year-Old Boy with Uncontrolled Sugar

Family Tree as per above tracing

Unique Case of A 25-Year-Old Boy with Uncontrolled Sugar
Unique Case of A 25-Year-Old Boy with Uncontrolled Sugar

CME INDIA Discussion (04/04/2022)

Dr. Awadhesh K. Singh, DM Endo., Kolkata:

  • Exclude Maternally inherited diabetes and deafness (MIDD).
  • Classical history! Check macula and ear.

Dr. Sujoy Majumdar, Endocrinologist, Kolkata:

  • Look out for associated
    • Myopathy
    • ECG abnormalities
    • Frank retinopathy
    • Frank proteinuria

Dr. B K Shukla, Internist, Arrah, Bihar:

  • This rare cause of diabetes should be suspected in the case of maternal inheritance and concomitant deafness.
  • The first clinical manifestations may appear at any age, but the disease is generally diagnosed in young adults with deafness appearing before diabetes.
  • Genetic testing is a must in this case.

Dr. Navin Burnwal, Nephrologist Ranchi:

  • Classical description of wolfram syndrome. Check for diabetes insipidus.
  • Only catch here is wolfram syndrome is autosomal recessive disease.

Dr. Palanikumaran, Physician and Diabetologists, Prof. of Medicine, Madurai Medical College:

  • Looks like WOLFRAM. Inheritance in wolfram is autosomal recessive.
  • But the inheritance pattern here is AD. So, this patient might be having WOLFRAM like AD syndrome, a rare variant. Unlikely to be MIDD since mother is involved.

Dr. Sujoy Majumdar, Kolkata:

  • Mitochondrial diabetes is usually transmitted maternally.
  • Mitochondrial DNA is transmitted by mothers to the offspring. Fathers can’t transmit mitochondrial DNA.
  • Also, most patients of Wolfram syndrome (DIDMOAD) present with Type 1 DM.
  • As per the description, this doesn’t look like a T1DM.
  • Mitochondrial encephalopathy with lactic acidosis and stroke like episodes (MILAS) apparently associated with this genetic mutation. However, no mention of DM as one of the comorbidities.
  • The only point against the DX is age. It usually presents in mid 30s.In this case ,17 is a bit early.
  • Though not impossible. Lowest documented age is 11. Also, though there is an initial response with SU, within 2 years many need insulin.
  • A genetic testing, if possible, should be done for confirmation of diagnosis.

Dr. P. D. Gokhale, Internist, Jamshedpur:

  • Only mitochondrial disorders caused by mutations in the mitochondrial DNA are exclusively inherited from mothers?
  • Mitochondrial diabetes in general is relatively rare in Asians ….so this case is certainly worth publication. Having a look at the case, I feel that ECG abnormalities should be looked into because the episode of presumed GTCS could actually be episode of syncope 2ary to arrhythmias.

Dr. Vijay Balaji K, Bangalore:

  • Anything unique in its management to diabetes sir?

Dr. Awadhesh K. Singh, DM endo., Kolkata:

  • Treatment like monogenic diabetes – SU drug of choice initially
  • Only important point that must be remembered during treatment of MIDD is not to use Metformin preferably because of high chance of MALA in these patients.
  • Be alert for Long QT syndrome which is unique

Dr. Basab Ghosh, Agartala:

  • Very nice presentation and fantastic inputs.
  • The prevalence is unknown, but MIDD accounts for 0.2-3% of all cases of diabetes.

Dr. Prabhat Agarwal, Prof of Medicine, Agra:

Case History Details

  • A 23 years old male known case of generalised tonic clonic seizure (GTCS) presented in emergency room in disoriented state. According to caregiver’s description and documents of previous hospital we made the diagnosis of Diabetic keto acidosis (DKA).
  • We shifted him in ICU and managed conservatively with insulin and intravenous fluids, he improved after 2 days but he complained of poor vision and hearing. We discharged him on basal-bolus regimen of insulin. His impaired vision and hearing started improving after one week and completely improved after 20 days. he is taking antiepileptics since childhood, currently on levetiracetam and sodium valproate. On taking family history her mother was also diabetic since the age of 23 years was managed on OHA and she had hearing impairment too. She expired at the age of 29 years.
  • Patient’s younger sister was also diagnosed diabetic at the age of 18 years, she also had hearing impairment but unfortunately, she expired at the age of 20 years due to some acute complication of diabetes. Patient’s father is non diabetic. Her maternal grand mom (naniji) was also diabetic diagnosed at the age of 40 years. Patient had two maternal uncles(mama) both were diagnosed diabetic at the age of 20 -22 years respectively and both had impairment in hearing. Elder maternal uncle expired at the age of 26 years. Her maternal aunt (mother’s sister/mossi) not tested for diabetes, expired at the age of 24 due to post-partum complications.
  • Thus, on the basis of his strong medical family history (maternal inheritance), hearing impairment and vision problem we suspected MIDD and sent her blood sample for genetic analysis, suggested A to G substitution at position 3243 of the mitochondrial DNA (m3243A>G).
  • For GTCS work up an MRI Brain was done which showed gyral swelling and hyperintensity, and CSF analysis for lactate level was high 57 mg/dl (10-22). Ophthalmic examination suggested maculopathy.
Unique Case of A 25-Year-Old Boy with Uncontrolled Sugar

Dr. Sujoy Majumdar, Kolkata:

  • Whatever I can infer there is some mitochondrial gene mutation. So, this should be consistent with the original diagnosis.

Dr. Awadhesh K. Singh, DM endo., Kolkata:

  • M3243A-G mutation is consistent with MIDD. Confirms diagnosis.
  • It’s not MELAS – it is MIDD.
Unique Case of A 25-Year-Old Boy with Uncontrolled Sugar

Quick Take Away

The abnormality of glucose metabolism in MIDD is associated with a gradual decrease in insulin excretion due to reduced ATP production in pancreatic b cells with abnormal mitochondria.
In MIDD, diabetes develops and hearing loss usually occurs in mid-adulthood.
Most often, the disease is diagnosed between the second and fifth decades of life.
This rare cause of diabetes should be suspected in the case of maternal inheritance and concomitant deafness.
Additional tests show normal or reduced levels of C-peptide and normal autoimmune markers.
Most often, hearing loss occurs before diabetes.
Coexistence of deafness and mitochondrial diabetes in patients with the m.3243A>G mutation is found in 60% of cases.
Be careful, avoid Sodium Valproate and Metformin in these cases.

CME INDIA Learning Points

  • Maternally inherited diabetes and deafness (MIDD) is a subtype of diabetes.
  • It is caused by a mutation of mtDNA.
  • Common clinical features of MIDD:
    • Neurosensory hearing loss,
    • A normal or low body mass index (BMI),
    • Short stature,
    • Presence of macular dystrophy.
  • The A3243G mutation in the mitochondrial tRNALeu (UUR) gene are known to cause mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) in some pedigrees.
  • The clinical characteristics of the MELAS:
    • Episodic vomiting.
    • Seizures.
    • Recurrent cerebral insults resembling strokes and causing hemiparesis, hemianopsia, or cortical blindness.
    • The most frequent symptoms are episodic sudden headache with vomiting and convulsions.
  • Why this case is not Wolfram syndrome?
  • Wolfram syndrome is an inherited condition that is typically associated with childhood onset insulin-dependent diabetes mellitus and progressive optic atrophy.
  • Many people with Wolfram syndrome also develop diabetes insipidus and sensorineural hearing loss.
  • DIDMOAD, which refers to diabetes insipidus, diabetes mellitus, optic atrophy, and deafness, is another name.
  • Most cases of Wolfram syndrome are caused by changes (mutations) in the WFS-1 gene
  •  Wolfram syndrome should be considered:
    • In anyone with diabetes mellitus and optic atrophy.
    • In anyone with low frequency sensorineural hearing loss.
    • In anyone with either diabetes mellitus or optic atrophy in addition to hearing loss or diabetes insipidus or bladder dysfunction or loss of sense of smell or a family member with Wolfram syndrome.
    • Molecular genetic testing for mutations in the WFS1 and WFS2 genes is available to confirm the diagnosis.
  • Diagnosis
    • Maternally inherited diabetes and deafness (MIDD) is caused by various mitochondrial DNA mutations.
    • The most frequent one is the 3243A > G in mitochondrial MTTL1 gene coding for mitochondrial transfer RNA Leucine (mt-tRNALeu (UUR)).
  • Prognosis for MIDD is better than in the case of MELAS syndrome and for other subtypes of diabetic mitochondrial disease.
  • Important Hearing Loss Pearls
    • Hearing loss in MIDD is sensorineural.
    • It is thought to be due to atrophy of the highly metabolically active cochlear striae vascularis because of reduced ATP formation by mitochondria (Naing et al., 2014).
    • Hearing loss generally precedes the onset of diabetes and is more common and severe in men.
  • Why these cases develop diabetes?
  • The A3243G mutation is present in all tissues, although heteroplasmy levels tend to be high in tissues with a low mitogenic activity, such as muscle.
  • It was originally considered that the main defect leading to diabetes is an altered glucose metabolism of muscle.
  • Further studies did not identify insulin resistance as a common factor in most carriers of the A3243G mutation, although insulin resistance has been reported in some carriers.
  • Hepatic glucose production may be another factor that becomes deregulated by the A3243G mutation.
  • A mitochondrial dysfunction in muscle is expected to lead to a higher lactate flux to the liver, fueling gluconeogenesis. At this time, no data are available on hepatic glucose production and its suppression by insulin in carriers of the A3243G mutation.
  • Thus, the loss of pancreas β-cells due to increased apoptosis, influx of fatty acids, and activation of stress-related kinases have been (which is also named secondary mitochondria dysfunction.)
  • Mitochondrial diabetes is thought to account for up to 3% of all diabetes mellitus cases.
  •  Depending on the degree of preservation of beta cell secretory capacity and peripheral muscle insulin sensitivity, the phenotype of mitochondrial diabetes may resemble that of type 1 or type 2 diabetes.
  • Mitochondrial diabetes may rarely present with diabetic ketoacidosis, and can be distinguished from other forms of monogenic diabetes including maturity onset diabetes of the young by the presence of multi-organ involvement, particularly pre-senile sensorineural hearing loss, maternal transmission, and later-onset diagnosis, typically affecting adults over 35 years.
  • Treatment Highlights
    • Various guidelines on diabetes care do not address this important subset of cases, and this diagnosis is easily missed.
    • There is paucity of data on tailored diabetes therapies for mitochondrial diabetes, particularly in the era of novel therapies including glucagon-like peptide-1 receptor agonist and sodium glucose co-transporter-2 inhibitors.
    • Avoid Metformin
      • Metformin-associated lactic acidosis (MALA) is a theoretically danger so better to avoid.
      • However, the incidence of this appears to be no higher than the background incidence of lactic acidosis in the general population (Schaefer et al., 2013)
      • Sulphonylureas are traditionally first-line therapy in patients with MIDD who are not insulin-dependent. The risk of hypoglycaemia with this therapy remains.
      • DPP4-inhibitors are considered safe and are well-tolerated in patients with MIDD.
    • Co-enzyme Q10 (CoQ10)
      • It is known to act as an electron carrier of the respiratory chain in mitochondria and has been shown to improve the mutation-associated dysfunction of the respiratory chain in mitochondria (Suzuki et al., 1998; Chinnery et al., 2006).
      • There has been some evidence that patients treated with CoQ10 have higher C peptide levels, reduced lactate levels following exercise and delay in progression of hearing loss compared with those treated with placebo.
    • Do not use Valproic Acid
      • Epilepsy is one of the most common presentations of patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). MELAS is typically caused by an A-to-G substitution at nucleotide position 3243 of mitochondrial DNA. Valproic acid, a common anticonvulsant, can actually increase the frequency of seizures in individuals with MELAS.
      • Status epilepticus (SE) in MELAS is associated with a stroke-lesion and it is usually refractory. Some cases respond favourably to Perampanel.

CME INDIA Tail Piece

Unique Case of A 25-Year-Old Boy with Uncontrolled Sugar


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