Henry A. Peters

Systemic Carnitine Deficiency Presenting as Familial Endocardial Fibroelastosis: A Treatable Cardiomyopathy

ENDOCARDIAL fibroelastosis is a cardiomyopathy of unknown origin that affects infants and young children. It is characterized by poor myocardial contractility with hypertrophy and dilatation of the...

THE TREATMENT OF ACUTE PORPHYRIA WITH CHELATING AGENTS: A REPORT OF 21 CASES

Excerpt Acute porphyria, especially its therapy, has challenged the clinician for years. The mortality rate when associated with severe neuropsychiatric manifestations is quoted as from 80 to 90%.1...

The benign proximal spinal progressive muscular atrophies.

Investigations by W o h l f a r t , F e z & Eliasson (1955), and by Kugelberg & Welander ( 1956) established proximal spinal progressive muscular atrophy as a distinct entity. The group of proximal spinal muscular atrophies (henceforth referred to as the WK\V (Wohlfart, Kugelberg, Welander) syndrome) now includes forms with both early and late onset, the latter cases without ( Wiesendanger 1960) and with bulbar syniptoms (Magee & DeJong 1960, Myrianthopoulos & B r o w n 1954, Tsukagoshi et al. 1965, Tsukagoshi e t al. 1966). Original reports of the early onset WI<W syndrome suggested probable autosomal recessive inheritance ( W o h l f a r t et al. 1955), but reports of late onset type of the WKW syndrome indicated an autosomal dominant mode of inheritance ( A r m s t r o n g e t al. 1966, Magee & DeJong 1960) with incomplete expression in certain families. The first reports described onset in early childhood or adolescence, hyporeflexialike weakness and atrophy predominantly of the proximal muscles, distinct fasciculations and slow progression over many years. The syndrome has often been mistaken for muscular dystrophy. Even W o h l f a r t (1942) reported a case of muscular dystrophy with fibrillary twitchings which we now know belongs to the WKW syndrome. Others have postulated a relationship between the WKW syndrome and amyotonia congenita. On purely clinical grounds amyotonias are divided into a malignant

Therapy of acute, chronic and mixed hepatic porphyria patients with chelating agents.

THE EFFECTIVENESS of the chelating agents 2,3-dimercaptopropanol ( BAL) and ethylenediamine tetraacetic acid (EDTA) in the therapy of acute, chronic, and mixed porphyria patients with severe neuropsychiatric symptoms has been reported in 15 of 20 patients treated with these agents.’-3 Individual cases have been cited4v6 in which BAL therapy seemed effective in arresting advancing symptoms of acute porphyria. Schrumpfs reported that a case of chronic porphyria with cutaneous symptoms benefited under BAL therapy. Paul and ThyressonT reported that a case of chronic porphyria improved with BAL therapy, while Dean* treated an acute porphyric patient with BAL for one day and felt it was ineffective. Kehoe, Rudensky, and Reynolds9 likewise treated one of two acute porphyric twins with low dosage of BAL for ten days but felt it was ineffective, although subsequently the patient went on to recovery from neurologic and psychiatric symptoms without other medical therapy during hospitalization. A mixed porphyric with porphobilinogenuria (included in a previous series) was reported in detail by Woods, Peters, and Johnsonlo to illustrate the favorable influence of EDTA administered initially by the intravenous route, followed by maintenance on oral EDTA therapy, resulting in continued recovery and protection from cutaneous symptoms. This report is to re-emphasize the effectiveness of chelation therapy in hepatic porphyria. Evidence will be presented to indicate the apparent existence of a porphyric-schizophrenic syndrome; another group of patients, who were clinically acute porphyrics but excreted porphobilinogen rarely, will be designated the “paraporphyric” group. It would appear that the chronic and mixed porphyric consistently excreted urinary copper in excess, while the acute porphyric often showed zinc diuresis before and during chelation treatment. Finally, an alteration of tryptophan metabolism was seen in the acute, chronic, and mixed hepatic porphyric, the porphyric-schizophrenic, and the “paraporphyric” patient. Watson11 divides porphyria into two major forms: first, the porphyria erythropoietica, in which the metabolic error resides in the bone marrow with onset in infancy of mutilating photosensitive dermatitis, and second, the hepatic porphyrias which he subdivides into acute, cutanea tarda, mixed, and latent forms. Acute hepatic porphyria, inherited as a mendelian dominant, is characterized by recurrent gastrointestinal, psychiatric, and neurologic symptomatology occurring singly or in combination. Whereas erythropoietic porphyria is rare, we are of the opinion that hepatic porphyria is much more common than suspected. Hepatic cutania tarda porphyria is manifested by the late onset of photosensitive cutaneous lesions. Hepatic mixed porphyria incorporates a combination of the cutaneous and acute varieties in which cutaneous, neurologic, psychiatric, and abdominal symptomatology appear in varying combinations. Latent forms of the disease exist. Increased delta-amino levulinic acid in the urine in acute porphyrics, as reported by Granick and Vanden Schrieck’z and by Mauzerall and Granick,13 stimulated us to utilize the quantitative determination of delta-amino levulinic acid, a porphobilinogen precursor, as a useful screening device. Eleva-

Acute Cerebellar Syndrome Secondary to Infectious Mononucleosis in a Fifty-two Year Old Man

Excerpt The case of infectious mononucleosis presented is of interest in that it occurred in a patient in the older age group, and that the central nervous system involvement manifested as an acute...

Intermittent negative pressure ventilation in the treatment of respiratory failure in progressive neuromuscular disease

Five men with degenerative neuromuscular diseases (three with amyotrophic lateral sclerosis [ALS] and two with Duchennes muscular dystrophy [DMD]) who had respiratory failure were treated with intermittent negative pressure ventilation (NPV). One patient with ALS in severe acute respiratory failure was successfully treated with NPV alone. This patient and two other ALS patients in chronic respiratory failure with Paco2 elevation stabilized or improved their vital capacity (VC) and lowered their Paco2 after 5 to 11 weeks of therapy. Finally, intermittent NPV was used to replace 24-hour positive pressure ventilation in two patients with DMD. It is concluded that intermittent NPV may stabilize or temporarily improve the respiratory status in patients with progressive neuromuscular diseases.

Porphyria: Theories of Etiology and Treatment

Publisher Summary Dermatological symptoms in acute porphyria may include a malar flush over the butterfly area. Some patients may show a dusky, diffuse complexion described as metallic, while several cases have diffuse melanosis. This chapter describes the theories of etiology and treatment of porphyria. Studies suggest that natural porphyrin substances and precursors are not toxic in themselves, but that protoporphyrin and coproporphyrin naturally occur in the white matter of the central nervous system and in the peripheral nerves. Symptoms of acute intermittent porphyria can be explained on the basis of a deficiency of needed essential porphyrins that have (1) been withdrawn from the nervous system for purposes of chelation or (2) have failed to be replenished in the nervous system because of an enzymatic block (uroporphyrinogen synthetase) in the synthetic pathway leading to protoporphyrin and coproporphyrin 111.

Ketogenic effects of carnitine in patients with muscular dystrophy and cytochrome oxidase deficiency

The effects of a single oral dose of carnitine on fasting-induced ketosis was investigated in four normal individuals, five patients with muscular dystrophy, and one patient with a generalized cytochrome c oxidase deficiency. Plasma carnitine, free fatty acids, glucose, insulin, and glucagon were also measured. Normal individuals showed an average 0.09 mM increase in blood beta-hydroxybutyrate concentration during a 12- to 18-hr period of fasting and carnitine administration did not affect this response (average: 0.12 mM). Muscular dystrophy patients showed a greater fasting-induced elevation in beta-hydroxybutyrate (average 0.29 mM) and carnitine administration greatly enhanced this ketogenic response (average 0.84 mM). The cytochrome c oxidase deficient patient showed an even larger increase in beta-hydroxybutyrate with fasting (1.67 mM) and carnitine further augmented this ketotic effect (3.78 mM). Plasma free fatty acids were also elevated in patients that showed enhanced ketosis. Plasma glucagon concentration did not change, but insulin levels decreased during the 12- to 18-hr period of fasting; no major differences were found between controls and patients. These results indicate that some patients with muscular dystrophy and cytochrome c oxidase deficiency are more prone to develop ketosis than normal individuals and that carnitine administration enhances this response. Since both muscular dystrophy patients and the patient with cytochrome c oxidase deficiency had similar ketogenic responses, the data suggest that ketone body utilization may be impaired in these patients. The ability of L-carnitine to be ketogenic should be considered in the treatment of these patients.

Serial in vivo determination of motor conduction velocity in tails of alloxanized non-diabetic and diabetic rats

Abstract The in vivo motor nerve conduction velocity was serially measured in alloxanized non-diabetic and diabetic rat tails. Conduction velocity in the alloxanized diabetic group reduced significantly in comparison to the value before the administration of alloxan and to that of the non-diabetic group. In the temporary diabetic group conduction velocity was decreased during the diabetic period, but returned to normal values in the non-diabetic period. Our results suggest that the decreased conduction velocity in alloxanized rats is not due to such a direct neurotoxic action of alloxan on the nerve conduction velocity, but rather the secondary results of a diabetic stage. The determination of conduction velocity in the rat tail nerve in vivo is a useful tool for the neurophysiological study of experimental neuropathy since it enables one to measure serially the conduction velocity in the same rat over many days without marked injury to the nerves.

204 SYSTEMIC CARNITINE DEFICIENCY PRESENTING AS FAMILIAL ENDOCARDIAL FIBROELRSTOSIS (EFE)

Familial occurrence of EFE suggests an inborn error of myocardial metabolism. We studied a family in which 4 of 5 sibs had EFE, apparently due to systemic carnitine deficiency(SCD). 3 of 5 died suddenly before age 3 with EFE at autopsy. Abnormal mitochondria were found in skeletal and cardiac muscle of the 3rd. The surviving 4th sib with EFE, without muscle weakness had a plasma carnitine level(PCL)of 4.8mcM/L(Nl,50±10), skeletal muscle carnitine level(MCL)of 30nM/gm(Nl,5000). On oral L-carnitine,(L-carnitine supplied by Sigma-Tau, Rome, Italy) PCL rose to 43.7mcM/L, exercise tolerance improved, mitral insufficiency resolved, ST-T changes partially reversed. Retrospective study of the 3rd sibs tissue found a serum CL of 4.5mcM/L, MCL of 30.9nM/gm, cardiac CL of 56.8nM/gm(Nl,5000), liver CL of 120.7 nM/gm(Nl,400). A 5th sib and the parents have low Nl PCL.Cardiac metabolism is almost entirely aerobic, with mitochondrial oxidation of fatty acids providing over 65% of energy supply. Carnitine is required for fatty acid transport into mitochondria. Deficiency causes fatty deposits in cytoplasm and depressed mitochondrial function. EFE may result from lowered cardiac mitochondrial activity with inadequate oxidative phosphorylation causing-poor myocardial contractility, compensatory dilatation and hypertrophy, subendocardial ischemia and fibrosis. PCL and muscle biopsy are indicated in EFE to exclude SCD, a treatable cause of cardiomyopathy.