What is the management plan for a patient with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) who also has acute intermittent porphyria (AIP) due to a hydroxymethylbilane synthase (HMBS) gene mutation?

Management of FTD-ALS with Acute Intermittent Porphyria and HMBS Mutation

Carbamazepine and other porphyrinogenic medications must be absolutely avoided in this patient, as the FDA explicitly contraindicates carbamazepine use in patients with hepatic porphyrias including acute intermittent porphyria due to risk of precipitating life-threatening acute attacks. 1

Critical Medication Safety Considerations

Drugs to Avoid Completely

• All porphyrinogenic medications must be discontinued immediately if this patient experiences any symptoms suggestive of an acute porphyric attack (abdominal pain, neuropsychiatric symptoms, neuropathy) 2
• Carbamazepine specifically increases porphyrin precursors and has triggered acute attacks in AIP patients 1
• Before prescribing any new medication for FTD, ALS, or other conditions, consult porphyria drug databases (www.porphyriafoundation.com/drug-database or www.drugs-porphyria.org) 3
• Avoid progestin-containing contraceptives or hormone therapies, as these can precipitate attacks 3, 4

Safe Medication Alternatives

• For neuropsychiatric symptoms of FTD, work with dementia subspecialists to identify non-porphyrinogenic psychotropic options 3
• Barrier contraceptive methods and non-hormonal IUDs are safe if needed 3

Baseline Evaluation and Monitoring Protocol

Initial Assessment

• Complete blood count and ferritin levels to assess for iron deficiency (common in young women with AIP) 2
• Liver function tests (aminotransferases elevated in ~13% during attacks and some asymptomatic patients) 3, 2
• Metabolic panel with eGFR to establish baseline renal function 2
• Neurologic consultation to differentiate ALS progression from potential porphyric neuropathy 3
• Blood pressure monitoring as chronic hypertension develops in some AIP patients 3, 4

Ongoing Surveillance

• Annual hepatocellular carcinoma screening (ultrasound ± AFP) as AIP patients carry increased HCC risk 4, 2
• Monitor for chronic kidney disease (chronic tubulointerstitial nephropathy or focal cortical atrophy) with annual eGFR 3, 4, 2
• Aggressive hypertension management if it develops, which may help prevent renal damage 3, 2
• Annual complete blood count, ferritin, and liver function tests 2

Patient Classification and Prophylaxis Strategy

Determine AIP Activity Status

This patient should be classified into one of four subgroups that determine management intensity 4, 2:

• Latent carrier: Has HMBS mutation but never had symptoms
• Asymptomatic high excretor: Elevated urinary porphobilinogen without symptoms
• Sporadic attack patient: Has had 1-3 attacks in lifetime
• Recurrent attack patient: ≥4 attacks per year

Prophylactic Treatment Indications

• If ≥4 attacks per year occur: Initiate prophylactic therapy with either weekly intravenous hemin OR subcutaneous givosiran 4, 2
• For menstrual cycle-related attacks: Consider hemin infusions once or twice during the luteal phase 4, 2
• If latent or asymptomatic: Annual follow-up with counseling about trigger avoidance 4

Acute Attack Management Protocol

Immediate Actions if Attack Suspected

Look for these specific symptoms: severe abdominal pain, seizures, hypertension, tachycardia, hyponatremia, new neuropsychiatric symptoms, or motor neuropathy 5

1. Stop all potentially porphyrinogenic drugs immediately, even before biochemical confirmation 2
2. Administer intravenous dextrose (at least 250g per day) to suppress hepatic heme synthesis 2, 5
3. Initiate intravenous hemin therapy early as the definitive treatment 2
4. Provide aggressive symptomatic management: opioid analgesics for severe pain (ensure they are porphyria-safe), antiemetics for nausea 2
5. Monitor and correct hyponatremia (occurs in 25-60% of acute attacks) 2

Lifestyle and Trigger Avoidance

Dietary Management

• Maintain adequate caloric intake and avoid prolonged fasting or crash dieting 3, 4
• Avoid bariatric surgery as it has triggered attacks 3
• Carbohydrate loading during early attack stages lacks evidence for benefit 3

Substance Use

• Avoid alcohol and smoking, particularly if the patient develops recurrent symptoms 3, 4
• Latent carriers may tolerate moderate alcohol without inducing symptoms 3

Stress Management

• Manage stress appropriately as it can precipitate attacks 4
• This is particularly relevant given the psychological burden of dual FTD-ALS diagnosis

Special Considerations for Surgical Procedures

Perioperative Planning

• Inform all physicians about AIP diagnosis well in advance of any procedure 3
• Review all anesthetic agents to ensure they are porphyria-safe 3
• Consider prophylactic hemin infusion pre- and post-operatively for patients with recurrent attacks, though specific guidelines are lacking 3
• Ensure intravenous fluids contain adequate glucose 3

Definitive Treatment Options

Liver Transplantation

• Orthotopic liver transplantation is curative and should be considered for patients with severe, disabling attacks refractory to hemin therapy 4, 2
• This may be particularly relevant if attacks become uncontrollable and significantly worsen quality of life beyond the FTD-ALS burden

Combined Organ Transplantation

• Combined liver-kidney transplantation may benefit patients who develop both recurrent attacks and end-stage renal disease 4, 2

Genetic Counseling and Family Screening

• Provide genetic counseling about autosomal dominant inheritance pattern 3
• Screen first-degree relatives for HMBS mutations to identify asymptomatic carriers 5, 6
• Note that penetrance is extremely low (~1% of heterozygotes develop symptomatic attacks), so most mutation carriers remain asymptomatic lifelong 7
• Identified carriers should receive counseling about trigger avoidance even if asymptomatic 3

Integration with FTD-ALS Management

Neuropsychiatric Symptom Management

• Work with dementia subspecialists to manage behavioral symptoms of FTD using only porphyria-safe medications 3
• Implement non-pharmacologic behavioral interventions as first-line for agitation, aggression, or other neuropsychiatric symptoms 3
• Use caregiver education, communication strategies, meaningful activities, and environmental modifications 3

Pain Management Considerations

• For ALS-related pain or FTD-related agitation, ensure all analgesics and psychotropics are verified as porphyria-safe before use 2
• Untreated pain can worsen behavioral symptoms in dementia 3

Monitoring Disease Progression

• Neurologic consultation helps differentiate ALS motor progression from potential porphyric motor neuropathy 3
• Nerve conduction studies and EMG may be needed if chronic neuropathic pain or unexplained weakness develops 3