GENERAL MEDICINE CASE DISCUSSION

[14 MAY 2020]

ROLL NO - 38

The case given was of  - 42 y/o female diagnosed with GLUCOSE 6 PHOSPHATE DEHYDROGENASE AND ADENOSINE MONOPHOSPHATE DEAMINASE DEFICIENCIES WITH VARIOUS OTHER PROBLEMS.

Case reference - https://classworkdecjan.blogspot.com/2019/05/42-f-with-severe-regular-edema-with_17.html?m=1

My basis of Prioritizing -

Pt wants to continue hiking and pursue her ambitions without increased / severe somatic and mental symptoms and according to me, most problematic symptoms are

• Frequent fluctuation of weight
• Shortness of Breathe
• Weakness, Numbness, Non-functioning of her limbs 
• Severe Blinding and vertigo inducing headaches
• Decreased/Absent REM sleep

MY EXPLANATION TO HER SYMPTOMS AFTER ACQUIRING THE DIAGNOSIS IS AS FOLLOWS 

[A] G6PD DEFICIENCY 

G6PD is the most important enzyme in HMP Shunt Pathway as it is responsible for the        formation of NADPH and is a part of oxidative and irreversible part of the reaction. 
Moreover being the first step of the reaction.

HMP SHUNT is ONE OF THE major sources of NADPH. And has the following funtions - 

1. Reductive biosynthesis of cholesterol, steriods, fatty acids
2. Free radical scavenging in RBCs, Lens, and keeping Fe in ferrous state in Hb.

SYMPTOMATOLOGY AND DIAGNOSIS PERTAINING TO G6PD

• Hemolysis - Severe jaundice at birth, edema in face/neck/trunk, Severe reaction to sulfa drugs and anti-malarial agents, Favism ; Pallor, Icterus [some cases], Edema, Hepato-splenomegaly [cannot be seen in case of increased edema]
• Investigations- [That are generally done, not this case in particular]

1. Complete Blood Count - Heinz Bodies seen in active disease
2. Reticulocyte count
3. Serum LDH - Elevated in case of Hemolysis 
4. Total, Direct and Indirect Hemoglobin 
5. Coombs Test - negative as G6PD is not immune mediated 
6. Beutler Flourescent Spot Test - Rapid test for visual identification of NADPH produced by G6PD under UV Light. [false negative in active hemolysis; also done in GALACTOSEMIA]

TREATMENT

• Avoidance of Foods, Drugs precipitating hemolysis 
• Folic Acid Supplemtation to increase RBC turnover 
• Blood Tranfusion/Dialysis if indicated
• Protection from infections as they may precipitate Hemolysis - Vaccination

[B] AMPD1 DEFICIENCY

AMP Deaminase is responsible for converting AMP to IMP with the release of 1 ammonia molecule, in purine metabolism. Normally, during vigourous exercise 2 ADP FORM 1 ATP AND AMP. And the AMP produced is converted to IMP by AMPD. Deficiency of AMPD leads to accumulation of AMP which [a] spills into blood where liver enzymes take up ribose and phosphate and lead to accumulation of adenosine in muscle [b] ATP Synthesis is determined by decreased ATP and incresed AMPD and hence leads to decreased ATP synthesis.

SINCE THE PT HAS BOTH G6P AND AMPD DEFICIENCIES THE SYMPTOMS TO OXIDATIVE STRESS AND DEPLETED ENERGY SUPPLIES ARE MORE SEVERE.

SYMPTOMATOLOGY AND DIAGNOSIS PERTAINING TO AMPD1 DEFICIENCY

• Weakness, Fatigue, Muscle Pain,Intolerance to Exercise - Decreased Aerobic output and increased anaerobic output, Accumulation of adenosine in muscle fibres ,High level of lactate, Ammonia produced in the reaction is hypothesised for reduced fumarate available for Kreb's Cycle
• Decreased And dark Urine After exercise/extreme stress -  Lactate elevation in blood. It could be because of Carb-Rich meals which lead to increased blood glucose. The glucose in blood is taken up by Muscles and Serum Lactate increases. And is excreted in the urine. Happens when load on muscles is greater than the body's ability to recycle it back to glucose. It could have been dark due to carbohydrates being excreted along with lactate in a concentrated form [my hypothesis, might be wrong]
• Shortness of breath, Sudden waking up at night with palpitations - High glycemic index food leads to dumping of lactate  which leads to Tachypnoea, Delayed Gastric Emptying leading to Shock Lactic Acidosis leads to waking up at night with tachypnoea and palpitations
• Migraine - Lactate in urine leads to obligatory excretion of Magnesium. Leading to Hypomagnesemia. HYPOMAGNESEMIA is associated with PALPITATIONS, DECREASED INTELLECTUAL ABILITY, MIGRAINES, etc
• Anesthesia awareness - Anesthesia may lead to Malignant Hyperthermia in such patients and is contraindicated. 
• Sleeping Issues - Hardly any REM sleep leads to anxiety, intellectual deficit, decresed immunity and increased oxidative stress. Adenosine accumulation in brain leads to feeling of fatigue and should promote sleep but since here NADPH is low [ G6PD] and Glycine is Low [non-essential AA which is an excitatory and inhibitory Neurotransmitter responsible for falling asleep] - there is sleep disturbance
• Investigations 

1. History 
2. Ammonia levels post forearm execrcise - AMMONIA DOES NOT INCREASE IN AMPD1 DEF.
3. Genetic Testing

TREATMENT

1. Ribose - orally, 0.2g/kg/day ; Taken hourly provides direct but limited source of energy to cells

2. Creatine Monohydrate

3. Cemitidine - Decreases swelling and Improves Sleep

4. L-serine - Improves Sleep Initiation and Maintenance

5. Triptans - Migraine 

OTHER MUTATIONS and PROBLEMS

• MTHFR Mutation - Hyperhomocysteinemia which leads to increased risk of THROMBO-EMBOLIC EVENTS, Cognitive impairment and dementia, Increased Fractures in elderly
• WNK1 Mutation - Hereditary sensory neuropathy  - reduced ability to feel pain, Dysregulation of Cation Chloride Cotransporters in Kidney 
• VWF mutation - Heavy menstrual bleeding, Bruising
• PCOS - Dysmenorrhea, Ectopic Pregnancy
• Severe Infections of Kidney, Lungs

SYMPTOMS I COULD NOT REASON 

• Stuttering, Loss of left side function 
• High post meal cortisol
• Discharge from Left Nostril
• Vertigo like symptoms 
• Excessive hair growth
• Loss of vision 

MY EXPLANATION TO HER SYMPTOMS WITHOUT KNOWN HISTORY AND INVESTIGATIONS

PATIENT CENTRED APPROACH

1. SEVERE JAUNDICE AT BIRTH 

• Hemolysis [SCD/ Thalassemia/ G6PD] 
• Hemolytic disease of newborn/Rh Incompatility
• AV Malformations/ Sepsis
• TORCH infections/ Hep A/ Hep B
• Alpha 1 anti-trypsin deficiency

     2. INTOLERANCE TO MILK / VOMITING POST FEEDING

• Lactose Intolerance
• Obstruction in the gut [Hypetrophic Pyloric Stenosis, Esophageal Atresia]

     3. DECREASED SLEEP SINCE BIRTH 

• Inborn errors of metabolism
• Congenital Heart disease

     4. DIFFICULTY IN BREATHING 

• Severe anemia due to malnutrition and or hemolysis
• Congenital heart disease
• Asthma
• Anxiety

     5. HIGH WITH FLUCTUATION DUE TO EDEMA 

• Allergy
• Kidney Disease
• Hypothyroidsim
• Hypoprotenemia - Hepatic Cause
• Hemolysis 

     6. EXCESSIVE HAIR GROWTH 

• Hyperandrogenism 
• Hyperinsulinemia
• Hypoinsulinemia 
• Cushing's Syndrome
• Precocious Puberty due to infections 

     7. HISTORY OF SEVERAL INFECTIONS OF LUNGS, KIDNEYS

• Malnutrition 
• Hyperglycemia
• SCID
• Chronic Granulomatous Disease
• Multiple Myeloma 
• Cystic Fibrosis

     8. SEVERE REACTION TO SULFA DRUGS AND ANTI MALARIAL AGENTS

• Allergy
• Hemolytic Anemia [G6PD/6PGD Deficiency]
• Thrombocytopenia
• Stevens-Johnson Syndrome

     9. FREQUENT FRACTURES

• Anorexia
• Kidney disease
• Hormone related [ Cushings/ DM 1 or 2/ Adrenal Insufficency]
• Lactose Intolerance

    10. FAVISM

• Characteristic of G6PD Def. 

    11. INTOLERANCE TO EXERCISE

• Anemia 
• Cystic Fibrosis 
• Fibromyalgia
• Intracranial Hypertension
• AMPD1 Def.
• Cardiac Pathology

    12. SEVERE IMPAIRING HEADACHE

• Migraine
• Cluster Headache
• Temporal Arteritis 

    13. VERTIGO

• Migraine associated Vertigo
• BPPV
• Multiple Sclerosis
• Tumours/Infarctions at Cerebellopontine Angle

   14. TRANSIENT LOSS OF VISION

• Occlusion of vessel [CRAO/Ophthalmic Artery]
• Giant Cell Arteritis
• SLE
• Migraine
• Intracranial HTN
• Intracranial Tumour

   15. SPONTANEOUS NASAL DISCHARGE

• Cluster Headaches
• Allergy

   16. WEAKNESS, NUMBNESS, FATIGUE OF LIMBS

• Anemia
• B12 and or Folate Deficiency
• AMPD1 Def
• Fibromyalgia 

DIFFERENTIAL DIAGNOSIS 

• Chronic Granulomatous Disease
• Severe Combined Immuno Deficiency Disorder
• Multiple Myeloma
• Multiple Sclerosis
• McLeod Syndrome
• G-6-PD Deficiency
• 6-PGD Deficiency
• APMD1 Deficiency
• Cystic Fibrosis
• SLE
• Fibromyalgia
• Cushings Syndrome

INVESTIGATIONS THAT MIGHT PROVIDE SOME INSIGHT

• Complete Blood Picture, Complete Urine Examination
• Hematocrit, Peripheral Smear, Reticulocyte Count
• RBC Sickling Test, Hb Electrophoresis
• Serum Iron, Ferritin, TBIC
• Coombs Test - Direct, Indirect
• Anti nuclear antibody test
• LFT
• RFT
• Serum TSH, T3, T4
• RBG, Insulin Levels
• Serum FSH, LH, Estrogen, Progesterone, Prolactin, Testosterone
• Cortisol 
• Urine and Serum Electrolytes
• Bone Mineral Density
• Genetic Test

SOURCES

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4397399/
• https://en.wikipedia.org/wiki/Neonatal_jaundice
• https://en.wikipedia.org/wiki/Glucose-6-phosphate_dehydrogenase_deficiency
• https://en.wikipedia.org/wiki/Adenosine_monophosphate_deaminase_deficiency_type_1
• https://en.wikipedia.org/wiki/Magnesium_deficiency
• https://en.wikipedia.org/wiki/WNK1
• https://en.wikipedia.org/wiki/Hereditary_sensory_and_autonomic_neuropathy
• https://en.wikipedia.org/wiki/Shortness_of_breath
• https://en.wikipedia.org/wiki/Edema
• https://en.wikipedia.org/wiki/Hirsutism
• https://en.wikipedia.org/wiki/Precocious_puberty
• https://en.wikipedia.org/wiki/Immunodeficiency
• https://en.wikipedia.org/wiki/Osteoporosis
• https://en.wikipedia.org/wiki/Adrenal_insufficiency
• https://en.wikipedia.org/wiki/Migraine#Abdominal_migraine
• https://en.wikipedia.org/wiki/Vertigo
• https://en.wikipedia.org/wiki/Amaurosis_fugax