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NEUROMUSCULAR DISORDERS Porphyric Neuropathy Timely diagnosis and treatment and new medications to prevent attacks provide more options for treating acute hepatic porphyrias. By Rachana Gandhi Mehta, MD; Vanessa Baute Penry, MD; and Herbert Lloyd Bonkovsky, MD

There are 4 acute hepatic por- phyrias (AHPs), including 3 with dominant inheritance: acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), and (VP). The fourth AHP is a rare autosomal reces- sive disorder, 5ALA-dehydratase deficiency porphyria (ADP). The more common AIP, VP, and HCP have low penetrance and present with neurovisceral attacks, primarily in women during their child-bearing years. The rare ADP has close to full penetrance and presents in infancy or early childhood with impaired neurodevelopment and occasional neurovisceral attacks. Porphyric neuropathy (PN) has variable expression and severity and may progress to quadriparesis and respiratory weakness if diagnosis and treatment are delayed. Early diagnosis of AHP and avoidance or elimination of poten- tial precipitants can prevent neurologic complications. Broader understanding of AHP pathogenesis has led to development of new therapies, which we summarize in this review.

Pathogenesis The AHPs are inherited metabolic disorders caused by spe- cific deficiencies in the pathway that result in heme precursors d-aminolevulinic acid (ALA) and (PBG) accumulation in the . Heme Figure. The Heme Biosynthetic Pathway and Porphyria Treatment. production in the liver is tightly controlled by the rate-limiting In the mitochondria, glycine and succinyl-CoA are converted to enzyme ALA synthase-1 (ALAS1), the first enzyme of the d-aminolevulinic acid (ALA) by d-aminolevulinic acid synthase 8-step heme synthesis pathway (Figure). Common precipi- (ALAS1), the rate-limiting enzyme in the pathway; all are tants of acute neurovisceral attacks (eg, , , blue. In the , ALA is metabolized to porphobilinogen calorie deprivation, certain hormones, and porphyrinogenic (PBG) and then to heme; when an enzyme in this pathway is defi- drugs) induce ALAS1 messenger RNA (mRNA) expression and cient, ALA and PBG accumulate and have neurovisceral effects caus- increase neurotoxic heme precursor production (ie, increase ing porphyrias (red), including acute intermittent porphyria (AIP), ALA and PBG). Heme deficiency and direct ALA neurotoxicity hereditary coproporphyria (HCP), variegate porphyria (VP), and are thought to be mechanisms for neurologic effects of AHPs.1 5-ALA-dehydratase (ALAD)-deficiency porphyria (ADP). Currently used treatments (dark green) decrease ALAS1 activity by inhibiting Acute Porphyria Attacks production () or suppressing induction (heme, ) of Acute neurovisceral attacks are usually heralded by prodro- ALAS-1. Investigational treatments (light green) are being devel- mal symptoms of brain fog, anxiety, and restlessness followed oped to replace PBG deaminase (PBGD) activity.

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by visceral or extremity pain, and , and dysau- Although also are elevated during acute AHP tonomia.2 The sympathomimetic stage can lead to vasospasm attacks, these are nonspecific and must be collected simultane- of major arteries resulting in myocardial infarction, amaurosis ously with ALA and PBG to avoid misdiagnosis. Further tests fugax, reversible cerebrovascular syndrome (RCVS), or poste- to quantify levels of urine ALA, PBG, and levels in rior reversible encephalopathy syndrome (PRES). Fortunately, plasma, urine, and can determine the specific type of most attacks do not progress beyond this stage when diag- AHP. aids in confirming the specific diagnosis nosed and treated in a timely manner. Attacks that go unrec- and identifying at-risk family members. ognized, however, may progress to a fatal neuropathy. Porphyric neuropathy (PN) is a motor-predominant axonal Treatment neuropathy that begins symmetrically in the upper extremi- Attack Prevention ties, followed by lower-extremity involvement. Proximal Approximately 3% to 8% of people with AIP, often peri- muscles are more often affected, and PN can progress rapidly menstrual women, have recurrent severe attacks.2 Preventive to quadriparesis and respiratory involvement that can be fatal therapy of frequent attacks includes prophylactic intravenous if untreated. A less common pattern is a focal motor neuropa- (IV) heme (once weekly), ALAS-1 mRNA antagonists, and thy presenting with wrist and/or foot drop.3 Numbness over identification and elimination of precipitants (Table 1). the trunk and thigh and, less commonly, paresthesias in distal Intravenous Heme. Within 3 to 4 days of administration, IV extremities can occur; however, sensory symptoms are less heme normalizes ALA and PBG levels by suppressing hepatic common. Because of the acute onset and rapid progression ALAS1 induction.4 Although it is an “off-label” use, a single with associated dysautonomia, PN often is misdiagnosed as prophylactic treatment 1 to 4 times / month of 3 to 4 mg / kg Guillain-Barré Syndrome (GBS), delaying appropriate treat- of IV heme can prevent recurrent attacks.5 To prevent throm- ment for porphyria. Key differences of PN compared with GBS bophlebitis and coagulopathy, reconstitution of hematin with include axonal rather than demyelinating features, the absence 25% albumin and administration into a larger periph- of albuminocytologic dissociation in cerebrospinal fluid (CSF), eral or central vein are recommended.6 Other less common and lack of response to immunotherapy. Symptoms that war- side effects of heme include , malaise, hemolysis, anaphy- rant consideration of an AHP are listed in the Box.1 laxis, reversible acute renal tubular damage, and circulatory collapse.6,7 Repeated heme administration has been associated Diagnosis with and tachyphylaxis. The key to early diagnosis is appropriate inclusion in the Givosiran. A small inhibitory RNA (siRNA), givosiran silences differential diagnosis and testing a single random urine sample ALAS-1 mRNA with subsequent inhibition of translation and for ALA, PBG, and creatinine levels. A PBG level 4 times the expression of the ALAS1 protein. Lower levels of ALAS1 reduc- upper limit of normal is diagnostic of AHP and should prompt es levels of neurotoxic ALA and PBG.1 Givosiran was approved therapy. A 24-hour urine collection is unnecessary, can be dif- by the Food and Drug Administration (FDA) for treatment ficult to collect and process correctly, and can delay diagnosis. of AHPs in late 2019.8 The approved dosage of subcutaneous givosiran is 2.5 mg / kg once monthly. A missed dose should be Box. Key Features of administered as soon as possible, followed by monthly injec- tions thereafter. An expanded access program is also available. Acute Hepatic Porphyrias In a phase 3, double-blind placebo-controlled multicenter Visceral pain trial (n=94), participants with a history of recurrent AHP attacks (≥2 in the 6 months before enrollment) givosiran Psychiatric and central (CNS) symptoms (2.5 mg / kg monthly) treatment resulted in a 73% reduction Dark urine in mean annualized attack rate compared with placebo treat- (often severe [serum Na+< 125 mEq/L]) ment. More participants treated with givosiran had no attacks compared with those who received placebo (50% vs 16%). For New-onset those treated with givosiran, there was a 77% mean reduction Recent use of porphyrinogenic drugs or low-calorie diets in IV heme use and sustained lowering of urinary ALA (86%) Family history of acute (AHP) and PBG (91%) levels from baseline, greater reductions in daily worst pain, lower use, and improved quality of life9,10 Photocutaneous blistering lesions (in ~two-thirds of patients compared with those receiving the placebo. with variegate porphyria[VP] and ~one-third of those with The most common adverse reactions to givosiran are nau- hereditary coproporphyria) sea, injection site reactions, rash, and fatigue. Concerns regard- Any of the above symptoms in women of child-bearing age ing long-term use of givosiran include the possibility of hepatic should raise additional suspicion for AHPs or renal toxicity as elevated alanine transaminase (ALT),

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TABLE 1. PREVENTIVE TREATMENTS FOR ACUTE available from the American Porphyria Foundation HEPATIC PORPHYRIAS (www.porphyriafoundation.com/drug-database) and on a Therapies Administration/dose Mechanism mobile app at www.porphyriadrugs.com). Extreme dieting should be avoided and a well-balanced diet with ample car- Givosiran SC 2.5 mg/kg monthly Silence ALAS1 bohydrates (60%-70% of total calories) is recommended. mRNA Heme IV 3-4 mg/kg/day Supress hepatic Acute Attack Treatments 1-4 times/ month in 100 mL ALAS1 induction Treatment of an acute attack (Table 2) includes discontinu- human albumin (5%-20%), 15-30 ing potential triggers, providing symptomatic treatment, and minutes in larger or central vein using therapies to downregulate hepatic ALAS1. Milder attacks Liver Surgical (only for severe refrac- Tissue provides can be managed at home using narcotics, nonsteroidal anti- transplant tory cases) wildtype DNA inflammatory drugs (NSAIDs), and increased glucose intake to Hormones Oral GnRH analogue or low- Prevents avoid visits to the emergency department (ED). Appropriate dose estrogen-progestin in precipitating pro- diagnosis and prompt specific treatment are often delayed or cyclical attacks gesterone surge not provided at all and individuals may be labeled as “drug- seeking” because of frequent visits to the ED for pain. When Abbreviations: ALAS1, -aminolevulinic acid synthase 1; δ visceral or extremity pain becomes severe or when neurologic GnRH, gonadotropin-releasing hormone; IV, intravenous; complications ensue, hospitalization is necessary. Bulbar mRNA, messenger RNA. involvement and arrhythmia require close monitoring in inten- increased creatinine levels, and reduced estimated glomerular sive care units (ICUs). filtration rate (eGFR) have been seen. Repression of ALAS1 d-Aminolevulinic Acid Synthase-1 Downregulation. Both IV synthase in the liver also leads to downregulation of some heme and high-carbohydrate loading can be used to down- -P50s, especially CYP1A2 and CYP2D6; genotyp- regulate ALAS1. The IV heme treatment is more potent than ing of can be considered prior to treatment and glucose, decreasing ALA and PBG within 3 to 4 days to result care used in treating anyone with those cytochrome isotypes. in clinical improvement within 4 days.4 The standard regimen Adverse developmental outcomes were seen in animal studies for an acute attack is 3 to 4 mg / kg / day given as a 30-minute and givosiran has not been tested in pregnant women. The infusion into a larger peripheral or central vein for 4 to 14 days high annual cost (wholesale annual cost=$575,000) may also depending on a person’s clinical status. This treatment is the present barriers to the use of givosiran. safest to use during pregnancy, and early use prevents neu- Liver Transplant. A liver transplant (LT) provides nonmu- ropathy progression.6,14 tant (wildtype) DNA to correct the genetic defect and restore Glucose inhibits the induction of ALAS-1 and thereby functional enzyme for the heme pathway, resulting in normal reduces theproduction of ALA and PBG; however, the effect of PBG and ALA levels within 24 to 72 hours. An LT often results glucose is weak. Carbohydrate loading can be considered for in clinical remission and has proven efficacy for refractory AIP. milder attacks (eg, without paresis, , or hyponatremia) However, LT should be considered only as a last resort for or when an IV heme preparation is not available. Carbohydrate those with severe and recurrent attacks not controlled with loading is most effective when a dietary restriction has con- other treatments.11 An LT has been performed in people with tributed to the attack and can be administered as a high- AIP and in 1 person with VP with great success; no persons with HCP have been treated with a liver transplant to date. A TABLE 2. ACUTE TREATMENT OF single individual with ADP reated with an LT had complica- ACUTE HEPATIC PORPHYRIAS tions of the procedure that resulted in eventual death.12 Drug Dose and route of administration Hormone Therapy. Some women with AHP develop cyclic Heme Intravenous 3 to 4 mg/kg or 250 mg of heme attacks coinciding with the progesterone surge of the luteal daily in 100 ml human albumin (5%-20%) phase of their menstrual cycles. These attacks can be prevent- infused over 15-30 minutes in larger vein or ed by a gonadotropin-releasing hormone (GnRH) analogue or central vein for 4-14 days a low-dose estrogen-progestin combination contraceptive.13 Glucose Intravenous 10% dextrose in sterile water or Identifying and Eliminating Precipitants. High-dose oral con- 0.45% saline or oral 300-500 g/day of glucose traception, some (eg, erythromycin, trimethoprim, and ), (eg, , carbamaze- Discontinue Not applicable. Consult the mobile app at pine, , and valproic acid), excess alcohol, smoking, porphyrino- www.porphyriadrugs.com or fasting, infection, and stress are common precipitants of AHP genic drugs www.porphyriafoundation.com/drug-database attacks. A useful list of medications that precipitate attacks is for a full list of porphyrinogenic medications

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carbohydrate diet, glucose tablets, or oral dextrose solutions if TABLE 3. SYMPTOMATIC TREATMENT OF tolerated. Treatment with IV glucose (300-500 g / day as 10% ACUTE HEPATIC PORPHYRIAS dextrose in sterile water or 0.45% saline) is also an option.15 Safe Unsafe sugar and electrolyte levels should be monitored, and Pain (visceral or , pethidine, Meperidine, infection ruled out. If glucose infusions do not result in clinical neuropathic) oxycodone, buprenorphine, tramadol, lido- remission in 1 to 2 days or if the attack continues to worsen, methadone, fentanyl, caine, diclofenac, heme should be administered. NSAIDs, acetaminophen, or celecoxib, or Symptomatic Treatments. See Table 3 for symptomatic treatments.16-19 Early rehabilitation should be considered for individuals with AHP who develop weakness. Close monitoring Neuromuscular Gabapentin, early rehabilita- of respiratory, speech, and swallowing function is essential. symptoms tion; mechanical ventilation Elimination of Precipitating Factors. A thorough history to (neuropathy, for respiratory weakness; identify potential precipitants (medication, alcohol use, smok- pain, weakness) consider nasogastric tube ing, recent weight changes) of an acute attack should be con- and speech and swallow sidered. Any infections should be treated promptly. therapy for dysphagia Seizure Gabapentin, vigabatrin, Phenytoin, Investigational Treatments levetiracetam, lamotrigine, barbiturates, Replacement of deficient enzyme, mRNA, and DNA are lorazepam, or , emerging therapies being studied with promising but as yet or valproic acid unproven results. Nausea or , prometha- Domperidone, Protein Replacement. Selective administration of recom- vomiting zine, prochlorperazine, olan- metoclopramide binant human PBG deaminase (rh-PBGD) in animal models zapine, or ondansetron lowers plasma PBG levels, providing proof of concept for this Hypertension/ Beta-blockers, ACE inhibitor, Nifedipine approach.20 Pharmacokinetic and pharmacodynamic studies calcium channel blockers, of rh-PBGD-enzyme replacement in people with AHP who or, clonidine were asymptomatic transiently lowered PBG for 2 hours.21 More studies are required to determine dose, safety, and effi- Anxiety, Lorazepam, alprazolam, Diazepam, clon- cacy for use to treat AHPs. insomnia, or fluoxetine, paroxetine, or azepam, bupro- Transcript Replacement. Human-PBGD (hPBGD) mRNA restlessness pion, duloxetine, encapsulated in lipid nanoparticles administered via ortrazodone IV-induced dose-dependent protein expression in mouse , haloperidol, hepatocytes and rapidly normalized urine ALA and PBG excre- or olanzapine. tion in ongoing attacks. Multiple administrations to nonhu- / Bulk laxative, senna, man primates suggest that the hPBGD, selectively targeted to paralytic lactulose, or neostigmine 22 hepatocytes, may prove effective in the treatment of AIP. Infection Cephalosporins, carbapen- , Replacement. Liver-directed gene therapy using ems, monobactams, or macrolide, an adeno-associated virus (AAV)-vector encoding PBGD imipenem, meropenem, tetracyclines, or in mouse models of AIP restored normal hepatic-PBGD ertapenem, aztreonam quinolones activity and prevented acute attacks. A phase 1 study in individuals with AIP who had frequent attacks was safe and Abbreviations: ACE, angiotensin-converting enzyme; NSAIDs, improved symptoms and quality of life of some participants nonsteroidal anti-inflammatory drugs. but failed to reduce porphyrin precursors levels, likely because management of porphyrias. Givosiran, a small interfering of insufficient liver transduction at the doses tested.23 Another mRNA therapy, represents a novel and targeted treatment approach using nonviral gene delivery of plasmids encoding approach and is the only FDA-approved treatment for the PBGD in human and mouse PBGD-deficient fibroblasts result- prevention of recurrent disabling attacks. Whether givosiran ed in a high expression of functional PBGD.24 may also be effective for treating acute attacks requires fur- ther study. The delivery of rh-PBGD enzyme or its mRNA Conclusion is under study for new therapeutic approaches for AIP, to Timely diagnosis, prompt treatment, and elimination of restore levels of PBGD protein, and has shown promising potential precipitants can prevent neurologic complica- results in animal models. More studies of protein, mRNA, tions of AHP. Understanding genetic abnormalities and and DNA replacements are required to assess their efficacy pathogenesis of porphyria has opened new avenues in the in AHP patients. n

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Rachana Gandhi Mehta, MD Assistant Professor of Neurology Wake Forest Baptist Health Winston-Salem, NC

Vanessa Baute Penry, MD Associate Professor of Neurology Wake Forest Baptist Medical Center Winston-Salem, NC

Herbert Lloyd Bonkovsky, MD Professor of Medicine and Molecular Medicine and Translational Science Wake Forest Baptist Medical Center Winston-Salem, NC

Disclosures VBP reports no disclosures and GM and HLB have disclosures at www.practicalneurology.com

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