Doss Porphyria ( δ-Aminolevulinic Acid Dehydratase Porphyria ) Presenting with Acute Onset Flaccid Paralysis

δ–Aminolevulinic acid dehydratase porphyria is an autosomal recessive disorder of heme synthesis resulting from deficiency of δ-aminolevulinic acid dehydratase (ALAD). Patients present with fatal neurovisceral manifestations and motor neuropathy. Here we report a patient with rapidly progressive flaccid tetraplegia with respiratory and bulbar paralysis. The importance of early diagnosis, prompt treatment and screening of relatives is stressed.


Introduction
P orphyrias are rare metabolic diseases resul ng from altered ac vi es of specifi c enzymes of the heme biosynthe c pathway.δ-Aminolevulinic acid dehydratase porphyria (ADP), some mes termed as Doss porphyria results from a defi ciency of δ-aminolevulinic acid dehydratase (ALAD) and is inherited as an autosomal recessive trait.Only six cases have been confi rmed by muta on analysis.ALAD is the second enzyme in the heme biosynthe c pathway and catalyzes the condensa on of 2 molecules of aminolevulinate acid (ALA) to form a monopyrrole, porphobilinogen (PBG) 1 .The prevalence of heterozygous ALAD defi ciency was es mated to be <1% in Germany and ≈2% in Sweden 2 .Clinical presenta on of ADP includes autonomic, central, motor and sensory symptoms.We are repor ng a case of a 10 years male with ADP presen ng as neurovisceral symptoms.

The Case
A 10 years male from Western region of Nepal with normal developmental milestones and no prior neuro-visceral symptoms presented with history of severe abdominal pain for fi ve hours dura on associated with vomi ng and diffi culty in breathing.Eight hours later, he developed decreased level of consciousness.There was no history of fever, headache, seizures, and rashes, intake of canned food or drugs.There was no history of consanguinity or similar illness in family members.Pa ent was intubated at a district hospital because he was not maintaining satura on and then referred to our hospital.On examina on, GCS was 8/15, heart rate was 128 beats/min (reference range 70-110), and respiratory rate was 28 breaths/ min, BP: systolic at 70 th and diastolic at 50 th percen le, SpO 2 : 100% on T-piece ven la on.CNS examina on revealed 4 mm sluggishly reac ng pupils, normal cranial nerves, no signs of meningeal irrita on, decreased tone in both limbs with sluggish refl exes and upgoing plantars.Other systemic examina on was normal.
Inves ga on showed WBC: 11,300/ cu.mm with neutrophilic predominance, Hb: 13.2 g/dl, platelet: normal counts, ESR: 50 mm in 1 st hour.Peripheral smear showed normocy c normochromic RBC, C-reac ve protein: nega ve, normal electrolytes, urine, blood sugar, serum amylase and liver func on test (LFT).ABG analysis showed respiratory acidosis, Chest X-ray and CT scan head was normal.CSF analysis was not done as pa ent was haemodynamically unstable.During hospital stay, no fever or seizure occurred but there was persistent tachycardia and hypotension requiring inotropic support.On 3 rd day of illness he was kept on mechanical ven lator due to repeated desatura on.On 4 th day there was marked hypotonia with arefl exia and equivocal plantars.On 5 th day of illness, colour of urine changed to dark brown on exposure to sunlight (Fig: 1).Based on history, examina on and urinary fi ndings, a clinical diagnosis of porphyria was made and urine was sent for Porphobilinogen (PBG) and ALA (d-aminolevulinic acid).Urine ALA was 3.18 mg/dl (0.0-0.55 mg/dl); whereas Urine PBG was 0.051 mg/dl (< 0.10mg/dl).Change of colour of urine on exposure to sunlight, increased urine ALA and normal urine PBG suggested a diagnosis of ADP.So 300 grams of 10% dextrose was started.Erythrocyte ALAD could not be done as child developed persistent bradycardia and expired on 9 th day of admission.Erythrocyte ALAD ac vity and urinary ALA were planned in both parents but could not be done due to fi nancial constraints.

Discussion
Porphyrias are a group of inherited diseases caused by defi ciency of enzymes of the heme synthe c pathway, resul ng in accumula on of porphyrins and their precursors.They are classifi ed into hepa c porphyrias with neurological manifesta ons and erythropoie c porphyrias with no neurological symptoms.ADP, a type of hepa c porphyria is an autosomal recessive condi on resul ng from defi ciency of ALAD.Its prevalence in South East Asia and Nepal is not known; most cases are reported in adolescent males.
ADP presents with severe neurologic manifesta ons similar to our case 2 .The typical neuropathy in ADP is an acute or subacute motor axonopathy predominantly aff ec ng proximal muscles symmetrically and can lead to tetraplegia, with respiratory and bulbar paralysis 3 .Ini ally, tendon refl exes may be hyperac ve and become absent later as in this case.Weakness is usually preceded by episodes of abdominal pain secondary to autonomic neuropathy 4 .Abdominal pain is the most common manifesta on occurring in 85-95 % of cases whereas tachycardia is the most common clinical sign 5 .Other symptoms of autonomic dysfunc on include hyper or hypotension, diaphoresis and hyponatremia.In this case tetraplagia was preceded by abdominal pain, and during PICU stay persistent tachycardia and hypertension developed, which was followed by bradycardia and hypotension.
Acute Encephali s as a diagnosis was excluded as there was no fever, convulsions, bizarre movements, or hallucina ons, whereas weakness in descending pa ern and early bulbar involvement made Guillian-Bárre syndrome (GBS) less likely.
In our case urinary ALA was raised whereas urinary PBG was normal s ugges ng the diagnosis.Other causes of increased urine ALA were excluded.Normal LFT excluded acute hepa s, absence of history of chronic exposure, acute presenta on, absence of microcy c hypochromic anaemia excluded lead poisoning, however zinc protoporphyrin was not done for defi ni ve diagnosis.Late presenta on, normal odour and absence of hepa c and renal involvement excluded tyrosinemia type-I.

Confi rma on of diagnosis can be done by
erythrocyte ALAD which was not possible in our case as child died before the inves ga on could be done.Normal Urinary ALA of both parents along with halfnormal ac vity of erythrocyte ALAD would have established the diagnosis but it was not possible due to fi nancial constraints.
Management is symptoma c along with dextrose and hemin.Carbohydrate acts by down-regula on of heme synthesis whereas hemin replenishes the depleted heme pool and provides nega ve feedback on heme synthesis 5 .However hemin was not available in our part of the world.As this is an autosomal recessive disorder, gene c counselling could have been done and screening should be advised for other siblings as well.

Conclusion
Acute Porphyria should always be suspected in pa ents with gastrointes nal symptoms and neuropsychiatric manifesta ons.Families of these individuals should be subjected to suitable enzyme tests, to screen asymptoma c rela ves.

Fig 1 :
Fig 1: change of urine colour on exposure to sun Before and a er exposure to sun Before dextrose therapy (5 th day)