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Carnitine deficiency Acute postpartum crisis.

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6. Miillcr HR, Wuthrich R, Wiggli U,et al: The contribution of
computerized axial tomography to the diagnosis of cerebellar
and pontine hematomas. Stroke 6:467-475, 1975
7. Murphy M G Successful evacuation of an acute pontine
hematoma. Case repon. J Neurosurg 37:224-251, 1972
8. Nelson JR: Ocular bobbing Arch Neuml22:348-356, 1970
9. Scott WR, New PFJ, Davis KR, et al: Computerized nxial
tomography of inmacerebral and invnvencricular hemorrhage.
Radiology 112:73-80, 1974
10. Silverstein
Primary pontine hemorrhage, in Vinken PJ,
Bruyn GW (eds): Handbook of Clinical Neurology. Vascular
Diseases of the Nervous System, Pan 11. Amxerdam,
North-Holland, 1972, pp 37-53
11. Susv JO,Hoyr WF. h f f RB:Clinical spectrum of ocular
bobbing. J Neurol Neurosurg Psychiatry 33:771-775, 1970
u:
Carnitine Deficiency:
Acute Postpatturn Crisis
Corrado Angelini, MD,Edmondo Govoni, MD.
Mercedes M. Bragaglia, MS, and Ludovica Vergani, MS
Fig 2. CT scan one month foIhing the patient’s initialpresentation shows rrsolution of the area of inrreaseddmsity within
the pons. Thefourth uentric&is now normal in size and sbape.
Calcijkation in the bilateral dentate nrrclens is unchangedfm
tbe originalstudy.
awake [ l 11, as were 5 of Silverstein’s 50 patients with
PPH [lo].
Our patient showed the characteristic CT scan
findings of a hematoma, namely, a lesion of increased
density that shows progressive and complete resolution. Miiller et a1 [6] recorded these findings of pontine hematoma in 3 patients, 1 of whom survived
with severe neurological deficit. Computed tomographic evaluation of patients with intracerebral
hematoma is extremely accurate 1101. Miiller et al[61
reported a series of 900 patients in whom no falsenegative hematomas were seen. False-positive diagnoses of hematoma are reported in the presence of
high-density areas such as tumors, calcification, or
contrast-enhanced lesions. However, these can be
readily distinguished through the use of aneriography or follow-up CT scans.
References
1. Bodie HG: Ocular bobbing and opsodonus. J Neuro!
Neurrm~rgPsychiatry 35~739-742, 1972
2. Bosch PE, Kennedy SS, Aschenbrenrr CA: Ocular bobbing:
the myth of its localizing d u e . Neurology (Minneap)
25:949-953, 1975
3. Clark C, Stern R: Ocular bobbing with survid. J Neuml
Neurosurg Psychiatry 39:58-60, 1976
4. Fisher CM.Clinical syndromes in cerebral hemorrhage, in
Fields WS (ed): Pathogenesis and Treatment of Cerebrovascular Disease. Springfield, IL, Thomas, 1961, pp 318-342
5. Fisher CM:Ocular bobbing. Arch Neurol 11:543-545, 1964
558
A 16-year-old girl, previously in good health, developed progressive generalized muscle weakness following her !irst parturition. The neck and proximal
limb muscles were especially weak and painful. Carnitine (4-uimethylamino-3-hydroxybutyrate) was
markedly decreased in muscle, plasma, and urine. Dietary carnitine supplementation, 2.0 gm daily, was
followed by clinical improvement and decreased lipid
droplets in muscle biopsy. Together with previously
reported cases, 2 fatal, the patient’s illness emphasizes
the risk of p m g n ~ ~
in ywomen with carnitine deficiency.
Angelini C,Govoni E, Bragagha M M ,er al:
Carnitine deficiency: acute postpartum crisis. Ann
Neurol 4:558-561, 1978
Carnitine deficiency syndrome is the first biochemical entity identified (type 1 lipid storage myopathy)
in disorders of muscle lipid metabolism in man [7,8].
Genetic transmission has been demonstrated in one
family [ 2 0 ] . Sixteen cases of carnitine deficiency have
been reported up to the present. In 4 of these cases,
the patients died of either respiratory insufficiency,
heart block, or an acute metabolic disturbance [3, 6,
91. Two were young women who succumbed following norma1 pregnancy [3, 61, a premyopathic phase
From the Department of Neurology, University Hospital of
Padova, and che Institute of Clinical Electron Microscopy. Policlinico S. Orsolq Univeniry of Bologna, Bologna, I d y .
Accepted for publication May 15. 1978.
Address reprint requests to Dr Angelini, Department of Neurol-
om, Reed Neurological Research Center, UCLA School of Medicine, Los Angeles, CA 30024.
0364-5134/78/0004-0614$01.25 @
1978
I by C o d 0 Angelini
giving way to rapid deterioration followed delivery.
We report here a third p a t i e n t in whom the symptoms began p o s t p a r u n , but who recovered after
carnitine replacement therapy.
A 16-year-old-girl appeared in good health u p to her first
pregnancy. After an uneventful pregnancy and delivery,
she developed elevated temperature, vomiting, and pain on
her left flank. After dismissal from the hospital, she noticed
that she was fatigued, fell frequently, and could not climb
stairs without help. She was unable to sustain lactation due
to muscle weakness. Forty days after delivery, she experienced sore back and neck muscles and could not hold her
head upright. Six months after delivery. the patient was
unable even to chew or to raise her arms. She had ptosis,
experienced difficulty in talking, and was bedridden. This
was the high point of her weakness and lead to r e h o s p i d ization.
Neurological abnormalities were confined to the
neuromuscular system and included symmetrical weakness
of the shoulder and pelvic girdle muscles. Neck muscles
Fig 1 . (A) Electron micrograph of deltoid muscle biopsy showing
longitudinal accumulation of lipid droplets adjacent to mitochondria. ( B ) Electron mimograph of altered muscle with
perinuclear lipid collections and subsarcohmma1 mitochondria
with &nre cristae. Black bars equal I p.
were especially weak. Weakness of the trunk muscles was
associated with lumbar lordosis. Distal limb muscles and
the craniobulbar musculature were clinically normal. Tendon reflexes were normal. There were n o sensory deficits.
Mentation was normal. Laboratory examination revealed
elevated serum enzymes: serum glutamic oxaloacetic
transaminase, 389 units (normal, 8 to 33); lactic dehydrogenase, 1,150 units (normal, 100 to 190); creatine phosphokinase, 305 units (normal, 50 to 160). Other routine
laboratory tests, an electrocardiogram, hepatic function
tests, and thymic scan were all normal. Needle electromyography showed abundant spontaneous fibrillation in
the biceps, deltoid, and first interosseus muscles. Motor
unit potentials were of short duration and frequently
polyphasic. There was a normal interference pattern on
maximal effort. Repetitive stimulation of the ulnar nerve at
5 per second showed no myasthenic decrease.
Biopsy was obtained from the deltoid muscle under local
anesthesia and routinely processed for histological, histochemical, and ultrastructural study. A second biopsy was
performed on the quadriceps muscle five months after carnitine replacement therapy. In the first biopsy, fresh-frozen
sections revealed small, atrophic, vacuolated fibers in every
muscle bundle. The vacuoles contained refringent, nonstainable material and stained positively with oil red 0. With
trichrome staining a purple subsarcolemmal region appeared, and increased intermyofibrillar reddish material
was present. T h e NADH-tetrazolium reaction identified
Case Report: Angelini et al: Carnitine Deficiency 559
P l a m a Carnitine L v e h i n the Patient and i n Control and Pregnant Women.
Subjects
Mean
2
SD
No. of
Determinations
Significance
12.5-29.0
35.1-5 1.7
10
p c 0.01
22.7-35.7
25.1-38.2
22.1-32.7
25.0-44.3
5
8
3
5
Range
Carnitine-deficient patient
19.8 f 5.07
Female controls
41.8 f 5.75
Pregnant females at:
Sixth month
29.1 f 5.75
Seventh month
30.9 f 4.73
Ninth month
26.6 2 5.48
One week postpartum
34.8 f 8.23
‘Plasma carnitine is expressed as nnnomoks per milliliter.
SD srandard deviation; NS = not significant.
9
p < 0.01
p < 0.01
p < 0.01
NS
-
3.8 nmoVml and long-chain acylcarnitines, 2.5 nmoYml.
Our patient’s free plasma carnitine levels are compared
with those of normal control women during pregnancy and
postpartum in the Table.
ragged-red fibers from the intensively stained subsarcolemmal peripheral ring.
Semithin sections stained with toluidine blue showed
multiple vacuolated longitudinal spaces. Electron microscopic examinadon showed very low density vacuoles disposed in columns along the myofibrils (Fig la).The lipid
droplets were situated close to mitochondria Mitochondria
often showed a dense matrix and packed cristae. Lipid collections were seen near the nuclei (Fig IB).
Free carnitine in plasma and tissues was assayed by the
radiochemical method of Cederblad and Lindstedt [4]. and
the results were similar to findings with a spectrophotometric method [ 11. Acylcarnitine was measured in the patient’s
plasma, and total soluble carnitine (free and acetylcarnitine)
was assayed in muscle and plasma following alkaline hydrolysis as described by Pearson and Tubbs [16]. Free carnitine in the first biopsy was found to be 1.53 nanomoles
per milligram of noncollngenous protein (NCP). Shonchain acetylcarnitines were not found. Skeletal muscle carnitine levels in our laboratory range between 10 and 23
nmoYmg NCP. The patient’s plasma free carnitine level
was measured on seven consecutive days and ranged between 12 and 29 nmol/ml. Short-chain acylcarnitines were
Treatment
When the diagnosis of carnitine deficiency was established,
carnitine replacement therapy was begun. The patient was
given 2 gm of DL-carnitine orally. She was placed on a
low-triglyceride diet of 50 gm of lipid. Continuous improvement in strength followed the initiation of treatment.
After three months of carnitine supplementation. the agent
was discontinued for metabolic studies. An intravenous
load of 60 mg of DL-carnitine per kilogram of body weight
was administered (Fig 2). The initial peak carnitine level
was within normal limits, but after only six hours her
plasma carnitine had dropped below the range of control
subjects. Carnitine was evidently either metabolized or
Pig 2. Serum camitine k l ~ f i l h w i n gintravenous administration of DL-carnitine, 60 mgper kilogram. (Control 1 =
normalvolunteer; Control 2 = p a t i m t w i t h polymyalgia
rheumatica; Control 3 =patient w i t h toxic polyneuropathy.)
3
5 6 0 Annals of Neurology Vol 4
No 6 December 1978
b
6
TIME IN HOURS
12
- f
24
stored in a s s u e since the excretion measured in the urine
was only 11% of the intravenously administered load
(controls had 90 to 100% excretion).
A second biopsy revealed that fibers were only finely
vacuolated. There were no ragged-red fibers, and atrophic
fibers were scanty. The free muscle carnitine level did not
change significantly (1.69 nrnoUmg NCP); alkali-hydrolized
soluble carnitine (shorc-chain acecylcarnitines) was 2.56
nmoVmg NCP. Catnitine therapy with a mediumthain triglyceride diet (0.1 p of L-carnitine per kilogram of body
weight) was reinstituted and has been followed up to the
present. The patient has recovered her strength.
Discussion
The interesting feature of this case is the clear-cut
relationship between the onset of the disease and
pregnancy. Low carnitine stores can be depleted
postpartum through loss of carnitine in maternal milk
(normal carnitine content in mother’s milk is 40
pmol/L). However, our patient was never able to
sustain lactation. A possible factor influencing tissue
carnitine alteration could be hormonal changes postpartum, i.e., the sudden drop of progesterone and
estrogens and the rise in prolactin; but no present
evidence supports this speculation.
In our studies we observed a decrease of plasma
carnitine in pregnant women. This change seems due
not only to volume dilution but also to increased fetal
demand: higher cord blood carnitine levels than in
maternal blood have been reported at birth by Hahn
et al [ I l l , suggesting active transport of carnitine
through the placenta in fetal tissues.
In man, carnitine deficiency can present clinically
as either (1) muscle carnitine deficiency [ l , 7, 13, 15,
18-20] or (2) systemic carniane deficiency [3. 6 , 9,
141, in which the compound is reduced in muscle as
well as in liver, heart, and plasma. The low plasma
carnitine level in our patient suggests a diagnosis of
systemic carnitine deficiency, although proof could
be established only on the basis of a liver biopsy,
which the patient refused. The more restricted form,
or muscle carnitine deficiency, seems to have a better
prognosis, and some patients have responded well to
carnitine supplementation [ l , 12, 14, 181. There have
been reports of patients with the systemic disease
who did not benefit from carnitine replacement therapy [ 6 ] .Other attempted treatments have consisted
of prednisone and propranolol therapy [lo, 13, 201.
Although the carnitine supplementation does not restore the level of free carnitine in the tissue, it
seemed to be effective in our patient and has no apparent side-effects.
Recent evidence supports the existence of a
carrier-mediated active transport system for carnitine
associated with the sarcoplasmic membrane in muscle
[17], plasma membrane of liver cells [ 5 ] , and cultured
heart and fibroblast cells [ 2 ] . Therefore, the tissue
levels could depend on both plasma carnitine levels
and acetylcarnitine fluctuation. In fact, a relatively
large quantity of short-chain acetylcarnitines was
found in the second biopsy.
Supported by a grant from the Muscular Dystrophy Association.
~
_ _ _ _ _ _ _ _
____
References
1. Angelini C, Liicke S. Cantaruta P: Carnitine deficiency of
skeletal muscle: repon of a treated case. Neurology (Minneap) 26:633-637. 1976
2. Bohmer T, Eiklid K,Johsen J: Carnitine uptake into human
heart cells in culture. Biochim Biophys Acta 465:627-633,
1977
3. Boudin G. Mikol J, Guillard A, et al: F a d systemic carnitine
deficiency with lipid storage in skeletal muscle, heart, liver
and kidney. J Neurol Sci 30:313-325, 1976
4. Cederblnd G. Lindsredt S:A method for the determination of
carnitine in the picomole range. Clin Chim Acta 37:235-243.
1972
5. Christiansen RZ, Bremer J: Active transport of butyrobetaine
and carnitine into isolated liver cells. Biochim Biophys Acta
448:562-577. 1976
6. Cornelio F, Didonato S, Peluchetti D, et al: Fatal cases of lipid
storage myopathy with carnirine deficiency. J Neurol
Neurosurg Psychiatry 40:170-178. 1977
7. Engel AG, Angelini C: Carnitine deficiency of human skeletal
muscle with associated lipid storage myopathy: a new syndrome. Science 173:899-902, 1973
8. Engel AG. Angelini C, N e h n R: Identification of carnicine
deficiency as a cause of human lipid storage myopathy, in
Milhorar AT (ed): Exploratory Concepts in Muscular Dystrophy 11. Amsterdam, Excerpta Medica, 1974. pp 601-617
9. Engel AG. Banker BQ, Eiben RM:Carnitine deficiency: clinical. morpholwcal and biochemical observations in a fatal
case. J Neurol Neurosurg Psychiatry 40:313-322, 1977
10. Engel AG, Sicken RG:Lipid storage myoparhy responsive to
prednisone. Arch Neurol27:174-181, 1972
11. Hahn P, Skah JP,Secombe DW,et ak Carnitine conrent of
blood and amniotic fluid. Pediatr Re5 11:878-880. 1977
12. Hocking GP,Cavanagh NPC, Smyth DPL, et al: Oral treatment of c e t i n e myopathy. Lancet 1 3 5 3 , 1977
13. Isaacs H. Heffron JJA, Badenhont M: Weakness associated
with the pathological presence of lipid in skeletal muscle: a
detailed study of a patient with carnitine deficiency. J Neurol
Neurosurg Psychiatry 39:1114-1123. 1976
14. Karpati G,Carpenter S. Engel AG. et al: The syndrome of
systemic carnitine deficiency. Neurology (Minneap)
25:16-24, 1975
15. Markesbery WR. McQuillen MP, Procopis PG. et al: Muscle
carnitine deficiency. Arch Neurol31:320-324, 1974
16. Pearson DJ, Tubbs P K Tissue levels of acid-insoluble carnitine in rat heart. Biochim Biophys Acta 84:772-773, 1964
17. Rebouche CJ: Carnirine movement across muscle cell membranes studies in isolated rat muscle. Biochim Biophys A a a
471:145-155, 1977
18. Scarlato G, Albizzad MG, Bassi S, et al: A case of lipid storage
myopathy with carniane deficiency. Eur Neurol 16:222-229.
1977
19. Smyth DPL, Lake DR, MacDermor J, et al: Inborn error of
carnitine metabolism (“carnitine deficiency”) in man. Lancet
1:1198-1133, 1975
20. Van Dyke DH,Griw RG, Markesbery W. et al: Hereditary
carnitine deficiency of muscle. Neurology (Minneap)
251154-159, 1975
case Report: Angelini et
d: Carnithe Deficiency 561
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