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Biotinidase deficiency Initial clinical features and rapid diagnosis.

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strated the presence of HSV-1 DNA sequences within
brain tissues of mice 13, 121 and humans 18, 121 who
were free of clinical disease. Previous work from this
laboratory { 5 } has also shown that high titers of certain
HSV-1 strains can be recovered from brains of asymptomatic mice inoculated intracerebrally. Clearly, additional work must be done to establish the true incidence of subclinical CNS infections associated with
herpesviruses.
R. D. D. is supported in part by a New Investigator Research
Award, NS20742, from the National Institute of Neurological and
Communicative Disorders and Stroke and by a generous grant from
The Joe and Emily Lowe Foundation, West Palm Beach, FL. J. M. is
supported in part by N I H Grant CA-34980.
The authors thank Ms. Joanne Rush and Ms. Sunita Mutha for
enthusiastic technical assistance and Ms. Grace Stauffer for manuscript preparation.
References
1. Bale JF Jr: Human cytomegalovirus infection and disorders of
the nervous system. Arch Neurol 41:310-320, 1984
2. Baringer J R Herpes simplex infection of the nervous system. In
Vinken PJ, Bruyn GW (eds): Handbook of Clinical Neurology,
Vol 32. Amsterdam, North Holland, 1978, pp 145-159
3. Cabera VC, Wohlenberg C, Openshaw H, et al: Herpes simplex
virus DNA sequences in the CNS of latently infected mice.
Nature 228:288-290, 1980
4. Dix RD, Lukes S, Pulliam L, Baringer JR: DNA restriction
enzyme analysis of viruses isolated from cerebrospinal fluid and
brain-biopsy tissue in a patient with herpes simplex encephalitis
(letter). N Engl J Med 308:1424, 1983
5. Dix RD,McKendall RR,Baringer JR. Comparative neurovimlence of herpes simplex virus type 1 strains after peripheral or
intracerebral inoculation of BALBk mice. Infect Immun
40:103-112, 1983
6. Dix RD, Waiaman DM, Follansbee S, et al: Herpes simplex
virus type 2 encephalitis in two homosexual men with persistent
lymphadenopathy. Ann Neurol 17:203-206, 1985
7. Fishman RA: Cerebrospinal fluid in diseases of the nervous
system. Philadelphia, Saunders, 1980, pp 196-197
8. Fraser NW, Lawrence WC, Wroblewska 2, et al: Herpes simplex type 1 DNA in human brain tissue. Proc Natl Acad Sci
USA 786461-6465, 1981
9. Levy RM, Bredesen DE, Rosenblum ML: Neurological manifestations of the acquired immune deficiency syndrome (AIDS):
experience at UCSF and review of the literature. J Neurosurg
62:475-495, 1985
10. McKendall RR, Klawas HL: Nervous system complications of
varicella-zoster virus. In Vinken PJ, Bruyn GW (eds): Handbook of Clinical Neurology, Vol 34. Amsterdam, North Holland, 1978, pp 161-183
11. Nahmias AJ, Whitley RJ, Visintine AN, et al: Herpes simplex
virus encephahtis: laboratory evaluations and their diagnostic
significance. J Infect Dis 145:829-836, 1982
12. Sequiera LW, Jennings LC, Carrasco LH, et ak Detection of
herpes simplex viral genome in brain tissue. Lancet 1:609-612,
1979
13. Shaw GM, Harper ME, Hahn BH, et ak HTLV-Ill infection in
brains of children and adults with AIDS encephalopathy. Science 227:177-182, 1985
14. Snider WD, Simpson DM, Nielson S, et al: Neurological com-
plications of acquired immune deficiency syndrome: analysis of
50 patients. Ann Neurol 14:403-418, 1983
15. Tucker T, Dix RD, Katzen C, et ak Cytomegalovirus and herpes
simplex virus ascending myelitis in a patient with the acquired
immune deficiency syndrome. Ann Neurol 18:74-79, 1985
16. Whitley RJ, Soong SJ, knneman C, et al: Herpes simplex encephalitis-clinical assessment. JAMA 247:3 17-320, 1982
Biotinidase Deficiency:
Initial Clinical Features
and Rapid Diagnosis
Barry Wolf, MD, PhD,"t Gregory S. Heard, PhD,"
Karen A. Weissbecker, BA,* Julie R. Secor McVoy, BS,*
Robert E. Grier, PhD,* and Robert T. Leshner, MDt
Biotinidase deficiency is the primary defect in most individuals with late-onset multiple carboxylase deficiency.
We have reviewed the presenting clinical features of 31
children with the disorder. Seizures,either alone or with
other neurological or cutaneous findings, are the most
frequent initial symptom observed. Other neurological
symptoms, such as hypotonia, ataxia, hearing loss, optic
atrophy, and developmental delay, are seen, in addition
to skin rash and alopecia. The disorder is also characterized by ketolactic acidosis and organic aciduria
Biotinidase activity may be diagnosed using a simple,
rapid, semiquantitative colorimetric procedure. Samples
of whole blood spotted on the same filter paper used by
most states to screen for phenylketonuria and other inborn errors of metabolism may be sent to an appropriate
reference laboratory. None of the common anticonvulsants or sedatives used to treat newborns and children
interfere with the test. Because biotinidase deficiency
can be treated readily with biotin, this disorder should
be considered in children with infantile seizures, especially in the presence of other characteristic neurological or cutaneous features.
Wolf B, Heard GS, Weissbecker KA, Secor
McVoy JR, Grier RE, Leshner R T Biotinidase
deficiency:initial clinical fearures and rapid
diagnosis. Ann Neurol 18:614-617, 1985
We have demonstrated that the activity of biotinidase,
the enzyme that cleaves covalently bound biotin from
partially degraded carboxylases and from biocytin, is
From the Departments of "Human Genetics, TPediatrics, and $Neurology, Medical College of Virginia, Richmond, VA 23298.
Received Mar 3, 1985, and in revised form Apr 18. Accepted for
publication May 8, 1985.
Address reprint requests to Dr Wolf, Department of Human Genetics, Medical College of Virginia, P. 0. Box 33, MCV Station, Richmond, VA 23298-0001.
614 Annals of Neurology Vol 18 No 5 November 1985
deficient in serum from children with the late-onset
form of multiple carboxylase deficiency 1151. The
neurological and cutaneous symptoms usually occur
during infancy or early childhood and may be accompanied by ketolactic acidosis and organic acidemia
caused secondarily by deficient activities of at least
three of the biotin-dependent enzymes: propionyl
CoA carboxylase, pyruvate carboxylase, and pmethylcrotonyl CoA carboxylase C163. If affected children are not treated, they may suffer irreversible
neurological damage or become comatose and die.
However, if the disorder is diagnosed early, the children may be treated effectively with pharmacological
doses of biotin. The characteristic symptoms have
been described in only a small number of patients.
Therefore, we now present a summary of the clinical
features, particularly the initial symptoms, of 31 patients with a diagnosis of biotinidase deficiency,
confirmed either in our laboratory or by others. We
also describe a simple procedure, designed originally
for newborn screening, by which a preliminary diagnosis of biotinidase deficiency can be made readily using dried blood on filter paper from individuals suspected of having the disorder. In addition, we have
demonstrated that the common anticonvulsive and
sedative medications administered to infants and children do not appear to interfere with the test.
NY), valproic acid (Abbott Laboratories, North Chicago,
IL), and sodium phenobarbital (Wyeth Laboratories, Philadelphia, PA) were diluted with 0.05 M potassium phosphate
buffer (pH, 6) to achieve concentrations two to three times
the maximum expected in whole blood. The solutions were
then developed in the presence of the enzyme substrate,
with and without p-aminobenzoate, and the results were
compared with standard and blank values under identical
conditions.
Subjects and Methods
Of 31 patients with biotinidase deficiency, 17 were diagnosed by our laboratory and the remainder by other laboratories throughout the world. The clinical and biochemical
features of the 17 children we diagnosed were obtained from
questionnaires filled out by the parents and from information
provided by their physicians 13, 147. The findings in the
other children with biotinidase deficiency were obtained
from a review of the literature [ l , 2, 4-6, 8-13].
Biotinidase activity in serum can be determined readily
using a quantitative colorimetric procedure involving the
measurement of p-aminobenzoate liberated from biotinyl-paminobentoate by biotinidase [15]. We have previously described a modification of this method that allows for simple,
rapid screening of biotinidase deficiency using the same
blood-soaked filter papers currently used in most neonatal
screening programs [7]. The blood spot is incubated overnight in a solution containing biotinyl-p-aminobenzoate. On
the next day, color developing reagents are added to detect
free p-aminobenzoate. Samples with biotinidase activity develop a distinct purple color, whereas those with deficient
activity remain straw colored. Recently, in a pilot newborn
screening program conducted in our laboratory in conjunction with the Virginia Department of General Services, we
have identified 2 infants with biotinidase deficiency using this
semiquantitative procedure E l 7).
Anticonvulsant medications and sedatives used in the
treatment of newborns and children with seizures were
tested for interference with the assay. Phenytoin and adrenocorticotropic hormone (Parke-Davis, Morris Plains,
Results and Discussion
The Table summarizes the clinical features of 31 children with biotinidase deficiency. There were 17 females and 13 males (the sex of the child in one report
was not identified) from 26 families, with consanguinity reported in 7 families. These findings, together with
the demonstration in parents of serum biotinidase activities which are between those of normal individuals
and affected children [15], are consistent with an autosomal recessive mode of inheritance for this disorder.
All of the children exhibited some of the symptoms
usually seen in patients with late-onset multiple carboxylase deficiency. The age of onset of symptoms
varied from 1 week to 2 years, with a mean age of 5.7
months. The most frequent initial neurological symptoms were seizures, usually myoclonic, and hypotonia.
Several patients presented with ataxia or hyperventilation; some also exhibited stridor or developmental
delay. Common nonneurological initial symptoms included skin rash (seborrheic or atopic), partial or
complete alopecia, and conjunctivitis. Some affected
individuals initially showed combinations of these
neurological and cutaneous findings.
More than 70% of the patients had seizures, hypotonia, skin rash, or alopecia at some time prior to
diagnosis and treatment. About half of the children
had ataxia, developmental delay, conjunctivitis, and visual problems, including optic atrophy. Hearing loss
was diagnosed in about 40%. The hearing loss, which
was usually high-frequency sensorineural, was often
demonstrated in patients before the initiation of biotin
treatment. Four of the affected children died while in
metabolic coma (several siblings of biotinidase-deficient children reported in the literature also died and
were probably also affected).
Over 80% of the patients had episodes of ketolactic
acidosis and organic aciduria. The most frequently observed abnormal urinary metabolite was 3-hydroxyisovaleric acid. Other commonly observed metabolites
included 3-methylcrotonylglycine, 3-hydroxypropionate,
and methylcitrate. When examined, mild hyperammonemia was usually present.
All children with the disorder who were treated
with pharmocological doses of biotin (10 to 20 mg
daily) improved clinically. The cutaneous manifestations usually resolved quickly, and the seizures and
ataxia usually stopped; the hearing loss and optic at-
Brief Communication: Wolf et al: Biotinidase Deficiency 615
Clinical a n d Biochemical Features of Biotinidase Dejciency
Feature
Initial
Symptom
Symptom
Occurred
at Any Time"
18/29
4129
7129
3/29
2213 1
18/31
27/31
613 1
3/29
0129
0129
19/31
12/29
17/31
7/29
6/29
4/29
0129
...
2 1131
2413 1
14131
8/31
25131
22/28
10131
25/29
~
Seizures
Ataxia
Hypotonia
Hyperventilation andor
stridor
Developmental delay
Hearing loss
Visual problems (including optic atrophy)
Skin rash
Alopecia
Conjunctivitis
Fungal infection
Metabolic acidosis
Ketolactic acidosis
Hyperammonemia
Organic aciduria
...
"Symptom may have been present but not reported in some of the
affected children described in the literame.
rophy appear to be less reversible than the other symptoms, however. Depending on the severity and frequency of episodes of metabolic and neurological
compromise, many children with developmental delay
rapidly achieved new milestones or regained those that
had been lost.
The biochemical abnormalities attributed to biotinidase deficiency are often life-threatening and appear to represent relatively late effects of the disorder.
The cutaneous symptoms and some of the neurological
findings are similar to those seen in various biotin
deficiency states and may result from a mild to moderate depletion of biotin when the residual carboxylase
activities are still adequate. Ketoacidosis and organic
aciduria usually occur only after protracted biotin
deficiency.
The anticonvulsants or sedatives tested did not cause
color development in the absence of substrate. Therefore, none of the medications appeared to interfere
with the biotinidase assay, indicating that tests performed on samples from infants and children being
treated with any of these drugs should not yield spurious results. Although sulfonamides contribute to color
formation in the developed reaction mixture because
of the presence of a free primary amino group, we
have previously shown that other drugs commonly
used in the newborn period, such as ampicillin, gentamicin sulfate, vitamin K, penicillin G, potassium, and
kanamycin sulfate, cause no interference [7]. We can
readily detect the presence of sulfonamides or other
interfering substances by testing a sample for color
development in the absence of substrate, however.
Our screening method for biotinidase activity offers
a simple, rapid way to obtain specimens from patients
suspected of having the disease. Since the enzyme activity in the blood spots is stable for up to 18 months,
the cards can be sent to an appropriate reference laboratory. If the sample has no activity on screening,
definitive diagnosis can be achieved subsequently by
quantitative analysis of enzyme activity in the child's
serum. Since the clincal features of biotinidase
deficiency are variable, even within the same family,
and the disease can be effectively treated, it is important to consider the diagnosis in those children exhibiting one or more of the characteristic neurological or
cutaneous symptoms.
This work was supported by grants from the National Institutes of
Health (AM 25675 and AM 33022) and from the National Foundation-March of Dimes (6-342).
We thank the physicians who sent us blood samples from their
patients to confirm the diagnosis of biotinidase deficiency and for
communicating the clinical information on those found to be affected. We also thank Rosa M. Vaughan for her excellent secretarial
assistance.
This is paper #262 from the Department of Human Genetics at the
Medical College of Virginia.
References
1. Baumgartner ER, Suormala T, Wick H, Bonjour JP: Biotinresponsive multiple carboxylase deficiency (MCD): Deficient
biotinidase activity associated with renal loss of biotin. J Inherit
Metab Dis 2(suppl 7):123-125, 1984
2. Charles BM, Hosking G, Green A, et al: Biotin-responsive
alopecia and developmental regression. Lancet 2:118-120,
1979
3. Cowan MJ, Packman S, Wara DW, et al: Multiple biotindependent carboxylase deficiencies associated with defects in Tcell and B-cell immunity. Lancet 2:115-118, 1979
4. DiRocco M, Superti-Furga A, Durand P, et al: Different organic
acid patterns in urine and in cerebrospinal fluid in a patient with
biotinidase deficiency. J Inherit Metab Dis 2(suppl 7):119-120,
1984
5. Gaudry M, Munnich A, Ogier H, et ak Deficient liver biotinidase activity in multiple carboxylase deficiency. Lancet 2:397,
1983
6. Greter J, Holme E, Koivikko M, Lindstedt S: Biotin-responsive
3-methylcrontonyl-glycinuriawith biotinidase deficiency. Abstracts of Free Communications, 22nd Annual Symposium, Sociery for the Study of Inborn Errors of Metabolism, 1984, p 8
7. Heard GS, McVoy JS, Wolf 8: A screening method for
biotinidase deficiency in newborns. Clin Chem 30:125-127,
1984
8. King M: Biotin-responsive stridor etcetera. Abstracts of Free
Communications, 22nd Annual Symposium, Society for the
Study of Inborn Errors of Metabolism, 1984, p 22
9. Leonard JV, Stealans JWT, Bartlett K, et al: Inherited disorders
of 3-methylcroronyl CoA carboxylase. Arch Dis Child 56:5359, 1981
10. Mienie LJ, Reineck CJ: Organic aciduria in neonatal biotinresponsive multiple carboxylase deficiency. Abstracts of Free
616 Annals of Neurology Vol 18 No 5 November 1985
11.
12.
13.
14.
15.
16.
17.
Communications, 22nd Annual Symposium, Society for the
Study of Inborn Errors of Metabolism, 1984, p 9
Munnich A, Saudubray JM, Coude FX, et al: Fatty-acidresponsive alopecia in multiple carboxylase deficiency. Lancet
1~1080-1081, 1980
Munnich A, Saudubray JM, Ogier H, et al: Deficit multiple des
carboxylases: Une maladie mktabolique vitamino-dependante
curable par la biotine. Arch Fr Pediatr 38:83-90, 1981
Schubiger G, GaRisch V, Baumgartner R, et al: Biotinidase
deficiency: clinical course and biochemical findings. J Inherit
Metab Dis 7:129-130, 1984
Thoene J, Baker H, Yoshino M, Sweetman L Biotin-responsive
carboxylase deficiency associated with subnormal plasma and
urinary biotin. N Engl J Med 304:817-823, 1981
Wolf B, Grier RE, Allen RJ, et ak Biotinidase deficiency: the
enzymatic defect in late-onset multiple carboxylase deficiency.
Clin Chim Acta 131:273-281, 1983
Wolf B, Grier RE, Allen RJ, et al: Phenotypic variation in
biotinidase deficiency. J Pediatr 103:233-237, 1983
Wolf B, Heard GS, Jefferson LG, et al: Clinical findings in four
children with biotinidase deficiency detected through a
statewide neonatal screening program. N Engl J Med 313:1619, 1785
Reversible Go-No Go
Deficits in a Case of
Frontal Lobe Tumor
M. E. Leimkuhler, PhD, and M.-M. Mesulam, MD
A 50-year-old woman had been treated for a psychiatric
disorder for three years. Findings during the elementary
neurological examination were essentially normal. However, a computed tomographic scan revealed a large
meningioma in the falx involving the medial aspects of
the frontal lobes bilaterally. Neuropsychological examination demonstrated deficits in complex attentional
tasks and also many errors of commission in the go-no
g o test. Following surgical excision of the tumor, her
go-no g o performance became normal. This patient
shows that damage to the medial frontal lobe can cause
deficits in go-no go performance, and that these deficits
can be reversible following resolution of the lesion.
Leimkuhler ME, Mesulam M-M: Reversible go-no
go deficits in a case of frontal lobe tumor.
Ann Neurol 18:617-619, 1985
The go-no go paradigm, widely used in physiological
psychology, requires the subject to emit a simple
motor response to one cue while inhibiting this reFrom the Division of Neurosciences and Behavioral Neurology,
Beth Israel Hospital, 330 Brookline Ave, Boston, MA 02215.
Received Feb 25, 1985, and in revised form Apr 23. Accepted for
publicarion Apr 23, 1985.
Address reprint requests to Dr Leimkuhler.
sponse in the presence of another cue. Animals with
lesions of the frontal lobe perform poorly in this task
because they cannot inhibit responses to the no go
stimulus. In monkeys these errors of commission are
particularly conspicuous after bilateral ablations in the
inferior frontal cortex 137. In dogs comparable deficits
have been described after bilateral lesions of the medial frontal lobe 111.
The relationship between go-no go performance
arid lesions of the frontal lobe has also been demonstrated in human subjects [2,43. Drewe [27 used the
go-no go paradigm to investigate 24 patients with unilateral lesions of the frontal lobe (12 left, 12 right). He
found that patients with lesions in the frontal lobe in
either hemisphere were more impaired than controls,
both in learning the task and in maintaining the differential responses to the two cues. Much of this impairment could be attributed to errors of commission.
Moreover, patients with lesions of the medial frontal
lobe in either hemisphere made more errors of commission than all other groups together, whereas patients with lesions in the dorsolateral or orbital frontal
lobe did not differ from controls.
It appears, therefore, that the go-no go performance in humans is most sensitive to damage in the
medial frontal lobe. The case described in this report
provides strong support in favor of this suggestion,
especially since the patient had the unique feature of
showing a marked improvement of go-no go performance upon partial resolution of her lesion.
Case Report
The patient is a 50-year-old ambidextrous woman who writes
with her right hand, has an eighth-grade education, and has
worked as a hospital cook and housekeeper. She had been
hospitalized for a psychiatric disturbance multiple times over
the course of three years, and had received several diagnoses
including atypical depression with hysterical traits. She responded poorly to neuroleptics and antidepressants. Her behavior over the years had been described as bizarre, disorganized, assaultive, and affectively labile. Prior to her last
admission, she had set her apartment on fire in an attempt to
get her estranged husband to return to her. A computed
tomographic (CT) scan performed on the basis of her atypical presentation revealed a large area of increased density
(enhanced by contrast material) anteriorly above the corpus
callosum on both sides of the falx. The medial aspects of the
frontal lobes were involved bilaterally, especially on the right
side, and there was some pressure effect on the surrounding
tissue (Figure, A).
Her elementary neurological examination had always
yielded entirely normal results. In specific, there were no
deficits of cranial nerves or sensorimotor function, or in the
level of consciousness. Reflexes were symmetrical and the
toes were flexor. In addition to severe impairments of reasoning, judgment, and insight, examination of her mental
state revealed major difficulties in all complex attentional
tasks, especially those that require the withholding of inap-
Brief Communication: Leimkuhler and Mesularn: Go-No Go Deficits in Frontal Lobe Tumor
617
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