Severe hydroxymethylbilane synthase deficiency causes depression-like behavior and mitochondrial dysfunction in a mouse model of homozygous dominant acute intermittent porphyria.

Acute intermittent porphyria (AIP) is an autosomal dominant inborn error of heme biosynthesis due to a pathogenic mutation in the Hmbs gene, resulting in half-normal activity of hydroxymethylbilane synthase. Factors that induce hepatic heme biosynthesis induce episodic attacks in heterozygous patients. The clinical presentation of acute attacks involves the signature neurovisceral pain and may include psychiatric symptoms. Here we used a knock-in mouse line that is biallelic for the Hmbs c.500G > A (p.R167Q) mutation with ~ 5% of normal hydroxymethylbilane synthase activity to unravel the consequences of severe HMBS deficiency on affective behavior and brain physiology. Hmbs knock-in mice (KI mice) model the rare homozygous dominant form of AIP and were used as tool to elucidate the hitherto unknown pathophysiology of the behavioral manifestations of the disease and its neural underpinnings. Extensive behavioral analyses revealed a selective depression-like phenotype in Hmbs KI mice; transcriptomic and immunohistochemical analyses demonstrated aberrant myelination. The uncovered compromised mitochondrial function in the hippocampus of knock-in mice and its ensuing neurogenic and neuroplastic deficits lead us to propose a mechanistic role for disrupted mitochondrial energy production in the pathogenesis of the behavioral consequences of severe HMBS deficiency and its neuropathological sequelae in the brain.

Penetrance and predictive value of genetic screening in acute porphyria.

OBJECTIVE: Penetrance, predictive value and female patients' perspectives on genetic testing were evaluated among Finnish patients with acute porphyria. We conducted a retrospective study to evaluate prognosis among at-risk female family members depending on the primary method of diagnosis. METHODS: The penetrance was calculated among 23 genetically heterogeneous families selected from the Finnish porphyria registry (n = 515, AIP 333; VP 182). We included kindreds with ≥9 patients in a family (range 9-23 patients, total 216 AIP; 129 VP). In 2015, the registry included 164 living female subjects between 14 and 85 years of age. A questionnaire was sent to 143 women, of whom 107 (75%, AIP 67; VP 40) replied. Female at-risk relatives (AIP 54; VP 30) were divided into two groups based on the primary method of diagnosis: mutation analysis (Group A, n = 40) or biochemical analysis (Group B, n = 44). RESULTS: Mean penetrance for all acute symptoms was 35% among AIP and 40% among VP families. In both study groups, the penetrance was higher among female (AIP 50%; VP 44%) than male patients (AIP 17%; VP 33%). Penetrance for hospitalized attacks was 30% among AIP families (range 10-80%, for women 41%) and 25% in VP (range 0-50%, for women 27%) demonstrating wide variations among families even with the similar genotype. Acute porphyria was diagnosed at the median age of 26 years (range 0-76 years) among female patients, commonly after the onset of acute symptoms. Diagnostic delay was an average of 7.4 years (range 1-30 years). Acute symptoms occurred at the median age of 24 years (range 10-57 years) and the first hospitalization at the median age of 26.5 years (range 15-57 years). At the onset of symptoms, 38% of the women were ≤ 20 years of age. According to the life table analysis, acute attacks occurred mainly during the following five years after the diagnosis and the attack risk diminished after 35 years of age. The annual risk for hospitalization due to an acute attack during fertile years was lower in Group A than Group B (0.002 vs. 0.010, p = .018), but the risk of all subsequent acute symptoms did not diminish (Group A 0.017 vs. Group B 0.019, p = .640). The cumulative risk of acute symptoms among asymptomatic patients at the time of diagnosis was 26.7% for Group A and 58.3% for Group B. The cumulative risk of the first subsequent attack requiring hospitalization after the diagnosis among all at-risk relatives was similarly less frequent in Group A than in Group B (OR 0.180; 95% CI 0.041-0.789, p = .041). If attacks were followed among symptomatic patients only, attack-free years were more frequent in Group A than in Group B. Patients preferred genetic screening before puberty to minimize the risk of acute symptoms and genetic discrimination was rare. 44% of the patients reported social, psychological or physical impairment due to acute hepatic porphyria, emphasizing the importance of supporting patients' emotional and resilience capacity. CONCLUSIONS: Among female at-risk relatives the annual risk for hospitalization due to an acute attack is <1% and for acute symptoms <2% during the fertile years. Genetic testing of relatives diminishes the risk of acute attacks. Diagnosis before symptom onset is key for subjects to remain asymptomatic during follow-up, and genetic screening should be done earlier than currently.

Acute porphyrias: a German monocentric study of the biochemical, molecular genetic, and clinical data of 62 families.

In Germany, analyses of clinical and laboratory features of patients with acute porphyrias are only available for hereditary coproporphyria (HCP) but not with other acute porphyrias, acute intermittent porphyria (AIP) and variegate porphyria (VP). The aim of the study was to analyze a large cohort of patients with particular focus upon quality of life aspects. Sixty-two individuals from separate families with acute porphyrias (57 AIP, 5 VP) were included into an observational study collecting biochemical, genetic, and clinical data. A questionnaire was designed to complete anamnestic information and to assess the influence on quality of life. Most frequent signs and symptoms or laboratory abnormalities were abdominal colicky pain, red coloration of urine, and hyponatremia. Depression or anxiety was reported by 61% or 52% individuals, respectively. Fatigue was mentioned as the most quality of life-limiting symptom. In 59/61 patients, mutations could be identified. 44% (20/45) had to be admitted to an intensive care unit. Heme arginate was used in 64% (29/45) of patients for treatment of acute attacks at least once and in 33% for long-term treatment with high frequency of administration. Serum creatinine values increased in 47% (7/17) of the patients with recurrent attacks. Our analysis confirms a substantial influence of the diseases on the quality of life on patients. Percentages of urine discoloration and intensive care unit admissions were much higher than in other reports. Long-term treatment with heme arginate requires careful monitoring of iron status and renal values.

Patient Perspective on Acute Intermittent Porphyria with Frequent Attacks: A Disease with Intermittent and Chronic Manifestations.

OBJECTIVE: Acute intermittent porphyria is a rare metabolic disorder that affects heme synthesis. Patients with acute intermittent porphyria may experience acute debilitating neurovisceral attacks that require frequent hospitalizations and negatively impact quality of life. Although clinical aspects of acute intermittent porphyria attacks have been documented, the experience of patients is not well known, particularly for those more severely affected patients who experience frequent attacks. The aim of the present study was to qualitatively characterize the experience of patients with acute intermittent porphyria who have frequent attacks, as well as the impact of the disease on daily living. METHODS: Patients with acute intermittent porphyria who experience frequent attacks were recruited and took part in 2-h qualitative one-on-one interviews with a semi-structured guide. Interviews were anonymized, transcribed, and coded. The inductive coding approach targeted textual data related to acute intermittent porphyria attack symptoms, chronic symptoms, and the impact of the disease. Saturation analysis was conducted to assess whether the research elicited an adequate account of patients' experiences. RESULTS: In total, 19 patients with acute intermittent porphyria were interviewed (mean age 40 years; 79% female). Eighteen patients (95%) experienced both attack and chronic symptoms. Patients described attacks as the onset of unmanageable symptoms that generally lasted 3-5 days requiring hospitalization and/or treatment. Pain, nausea, and vomiting were considered key attack symptoms; pain, nausea, fatigue, and aspects of neuropathy (e.g., tingling and numbness) were considered key chronic symptoms. CONCLUSIONS: In this study population of acute intermittent porphyria with frequent attacks, most patients had symptoms during and between attacks. In these patients, acute intermittent porphyria appears to have acute exacerbations as well as chronic day-to-day manifestations, and is not just intermittent as its name implies. As a result, patients reported limitations in their ability to function across multiple domains of their lives on a regular basis and not just during acute attacks.

Acute Intermittent Porphyria in the North of China: The Acute Attack Effect on Quality of Life and Psychological Condition.

BACKGROUND: Acute intermittent porphyria (AIP) is an autosomal recessive disorder with intermittent attacks. Patients with AIP are susceptible to impaired quality of life and psychological distress. OBJECTIVES: To document the clinical features of AIP and its impact on SF-36 and IES scores of AIP patients in China and to explore the variables associated with SF-36 and IES scores. METHODS: A single investigator collated data related to treatments and outcomes in 27 patients with AIP of PUMCH. A cross-sectional questionnaire survey including the SF-36, the IES-R, and demographic questions was conducted in the north of China. Differences in the QoL scale/summary scores and proportions in the QoL dimensions between patients and the general population were analyzed. Independent effects of chronic conditions and demographic variables on the SF-36 and IES-R were analyzed. RESULTS: AIP patients had considerably lower SF-36 scores than the general population (the PF score and MH were lower than normal, P < 0.05). Working had higher RP than staying at home (P = 0.02); "without acute attack" had higher PF and BP scores and PCS composite score (P = 0.001). The mean IES-R score of AIP was higher than normal (36.7 ± 11.8 points, P < 0.001), "without acute attack" had lower intrusion score than "with acute attack" (P = 0.03). CONCLUSION: AIP patients in China had impaired quality of life, especially in terms of physical health. The acute attacks coursed the posttraumatic stress disorder-related symptoms.

Psychiatric Aspects of Acute Porphyria: a Comprehensive Review.

PURPOSE OF REVIEW: The aim of this paper is to review psychiatric manifestations, comorbidities, and psychopharmacological management in individuals with acute porphyria (AP). RECENT FINDINGS: Recent literature begins to clarify associations between AP, schizophrenia, bipolar disorder, and other psychopathology. Broad psychiatric symptoms have been associated to acute porphyria (AP) and correspond to a spectrum of heterogeneous manifestations such as anxiety, affective alterations, behavioral changes, personality, and psychotic symptoms. These symptoms may be difficult to identify as being related to porphyria since symptoms may arise at any time during the disease process. In addition, these patients may present psychiatric conditions secondary to the disease, such as adjustment disorder and substance use disorders. Timely diagnosis and appropriate treatment of psychiatric manifestations positively impact the course of the disease.

[Altered orientation and aggressiveness in an 89-year-old woman]. / Wechselnde Vigilanz und Fremdaggressivität bei einer 89­jährigen Patientin.

An 89-year-old woman with Alzheimer's dementia was admitted because of altered orientation, aggressiveness and inability to take care of herself at home. Her patient history indicated that 14 days ago the battery of the pacemaker had be renewed. During that time the patient suffered from psychomotor alterations. Therefore, melperone had been initiated. Inspection of the urine and laboratory findings pointed towards an acute exacerbation of acute intermittent porphyria as a possible cause of the delirium. After discontinuation of melperone with additional parenteral therapy with physiological fluids, the signs of delirium significantly improved.

[State of dementia due to intermittent acute porphyria: a case report]. / Une porphyrie démentielle ou manifestations psychiatriques chroniques de la porphyrie. À propos d'un cas.

INTRODUCTION: Porphyrias are rare inherited disorders due to specific enzyme abnormalities of heme biosynthesis. We can classify them as hepatic or erythropoïetic, the type depends on the organ in which the enzyme is deficient. Among the hepatic forms, three of them are clinically characterised by acute abdominal pain and neuropathy, sometimes associated with psychiatric disorders. CASE REPORT: This 58-year-old woman has been hospitalized frequently since 1995 with depression, apathy, or for suicide attempts. She has a history of alcohol addiction and since 1992 suffers from non-insulin dependant diabetes. She had been treated by benzodiazepines and neuroleptic medication for several years. Psychiatric examination revealed persecution and megalomania delirium associated with a Capgras syndrome, confusion, disorientation, depression and blunted affect. Results of neurologic examination showed reduced deep tendon reflexes, and nerve conduction revealed sensitive neuropathy. Moreover, she lay down, remained non-responsive and resisted care. The whole clinical picture evoked early dementia. Coloured urine was noticed and porphyria tested. When the diagnosis of intermittent acute porphyria was made, she gradually improved by stopping the drugs not indicated for the case, and by treating her diabetes. A few months later, while hospitalized for a similar episode, she choked on her food and died, probably caused by autonomic neuropathy. DISCUSSION: Our hypothesis was that chronic and debilitating psychopathology may be due to acute intermittent porphyria. Probably, among patients treated for psychiatric illness, some of them may suffer from this enzyme abnormality. Above all, the psychopathology associated with intermittent acute porphyria is polymorphous such as atypical psychosis, schizoaffective disorder, depression, apathetic withdrawal, and in this case report dementia. In like manner, organic manifestations are numerous and varied, leading to erroneous diagnosis. We suspect that patients with porphyria are common among mentally ill subjects. Do we have to test all our psychiatric patients for porphyria? It seems that the prevalence of intermittent acute porphyria in the psychiatric patient population is 0.21%, whereas the prevalence in the normal population is from 0.001 to 0.002%. CONCLUSION: The early detection of porphyria may diminish morbidity and mortality rates, and perhaps heal some chronic atypical psychiatric illnesses.

An unusual suicide attempt: a case with psychosis during an acute porphyric attack.

The porphyrias are a heterogeneous group of disorders characterized by abnormal heme biosynthesis. Although all subtypes are rare, acute intermittent porphyria (AIP) is the most common form of the neuroporphyrias. Abdominal pain, peripheral neuropathy, and changes in cognitive function are the classical triad of an acute porphyric attack but the variability of the symptoms may interfere with the diagnosis of AIP. Delayed diagnosis and treatment of acute porphyric attacks, however, can be fatal or may cause long-term or permanent neurological damage. We hereby report a case of 45-year-old male with suicide attempt because of his psychotic symptoms during an AIP attack.

Acute intermittent porphyria: diagnosis per chance.

OBJECTIVES: To report a case of acute intermittent porphyria (AIP) diagnosed by chance during routine investigations. CLINICAL PRESENTATION AND INTERVENTION: A 21-year-old female presented with vague gastrointestinal symptoms. Upon admission, she was disoriented. Later she developed generalized seizures and was treated with phenytoin, but the condition worsened. Upon investigation, her liver function, renal function, blood sugar level and electrolytes were within normal limits. When kept for routine laboratory testing, the color change in urine prompted us to investigate for porphyria. It was positive for phorphobilinogen (PBG) and urophorphyrin. Since AIP had been diagnosed, the initial treatment with phenytoin was discontinued with a favorable outcome. A screening test for PBG in urine by Ehrlich's reagent was performed on the patient's mother and was positive. CONCLUSION: A high degree of suspicion at the laboratory can also determine the diagnosis of AIP, which is often missed by the clinician.

Acute intermittent porphyria: psychosis as the only clinical manifestation.

Acute intermittent porphyria (AIP) is the most common of the four forms of neuroporphyria. AIP mimics a variety of disorders and thus poses a diagnostic quagmire. Abdominal pain occurs in 90-95% of the attacks. Some patients develop psychiatric symptoms such as psychosis similar to schizophrenia. The diagnostic difficulty may lead to under-diagnosis of patients who present with strictly psychiatric symptoms. This assumption is supported by a high prevalence of AIP in psychiatric hospitals. Therefore, we encourage a high index of suspicion for AIP in psychiatric patients in order to prevent false psychiatric diagnosis. In addition we discuss psychotropic drugs that may exacerbate acute attacks in undiagnosed patients. We report a case in which the diagnosis of AIP was clouded by the presence of only psychiatric symptoms. The clue for diagnosis was an anamnestic detail of the use of a porphyrogenic drug prior to the admission. The diagnosis of AIP was supported by excess of alpha aminolevulinic acid (ALA) and porphobilinogen (PBG) in urine concomitantly with a decrease in porphobilinogen deaminase (PBGD) activity in erythrocytes. The diagnosis was further strengthened by the fact that the patient's father was identified as an AIP carrier. However, in the absence of typical organic symptoms of porphyria, one cannot definitely rule out the presence of schizophrenia in this patient in addition to AIR

[Acute intermittent porphyria as a problem in differential diagnosis]. / Akutna intermitentna porfirija kao deferencijalnodijagnosticki problem.

In this study the authors have stressed the multidisciplinary approach regarding the etiology of psychiatric disorders. This approach provides not only the quantitative but also the qualitative increase within the essence of psychic life and psychiatric disorders pointing out the integrity of biological, psychological and social in a human being. Many somatic diseases are followed by the psychiatric and neurological symptoms. One of these diseases is the acute intermittent porphyria (AIP) that is manifested with a wide spectrum of clinical manifestations and it is called "the great imitator". The AIP attacks are characterized by abdominal pains, neurologic and psychiatric disorders. The most important is to diagnose the disease at the onset. If not, many severe complications may occur, even the lethal outcome is possible. This case report has shown the significance of the above mentioned statements.

Self-rated psychosocial consequences and quality of life in the acute porphyrias.

A battery of self-report psychosocial measures was mailed to 116 patients who had been referred for clinical management (clinic attenders) or laboratory diagnosis (non-clinic attenders) to the London Supraregional Assay Service Centre for Porphyria over the past decade and who tested positive for porphyria. Usable replies were received from 81 (70%) patients. Our interest focused on the prevalence of psychosocial symptoms in acute porphyrias and the perceived effects of porphyria on quality of life and patient experience. Research questions examined included (i), lifestyle factors; (ii) life events; (iii) mental health; (iv) general health; and (v) perceptions of illness of patients receiving specialist clinical management compared to respondents referred for diagnostic investigations, between patients with latent or manifest symptomology and between patients with different types of porphyria. Patients with porphyria have an impaired quality of life, particularly manifest cases, compared to controls and to diabetic patients. Depression, and particularly anxiety, is more common than in the general population or general medical outpatient attenders. Quality oflife is lower in acute intermittent porphyria (AIP) than in other forms of porphyria and a significant number of patients had major life event consequences, e.g. failure to secure, or loss of, employment, limitation of family size. Patients attending a clinic providing specialist porphyria advice, management and counselling received some perceived lifestyle benefits.

[Adolescent crisis with cyclic abdominal complaints and regressive behavior]. / Adoleszentenkrise mit zyklischen Abdominalbeschwerden und regressivem Verhalten.

In this 18 year old female patient with adolescent crisis, psychic regression and cyclic abdominal pain, the diagnosis of an acute intermittent porphyria was made by positive urine finding of porphobilinogen, by low serum measurement of the enzyme urosynthase and the positive genetic mutation of this enzyme. The article gives a brief report of the pathogenesis, clinical findings, diagnostic tests and the current therapies being undertaken. Further, a list of medications which are indicated or contraindicated relating to the patient with acute intermittent porphyria is noted.

Psychiatric symptoms of inherited metabolic disease.

Inborn errors of metabolism often present with a variety of psychiatric symptoms. With improved diagnosis and treatment options, many patients have increased lifespans; consequently, issues of long-term quality of life are coming to the forefront. Mental health concerns are among these issues. To demonstrate the connection between the course of metabolic disease and its psychiatric manifestations, four different inborn errors of metabolism are reviewed: phenylketonuria, Wilson disease, acute intermittent porphyria, and metachromatic leukodystrophy.