Wolf, Barry. “Think metabolic” in adults with diagnostic
challenges: Biotinidase deficiency as a paradigm disorder. Neurology: Clinical Practice Volume 7(6),
December 2017, p 518–522.
Abstract: Neurologists should consider the possibility of an
inherited metabolic disorder in adults with neurologic symptoms that may or may
not mimic those seen in affected children, such as in the case of biotinidase
deficiency. Because many of these disorders are treatable, they must be
included in the differential diagnosis. Technologies, such as specific
biochemical analysis and whole exomic sequencing, can assist the clinician by
leading to the appropriate diagnosis and treatment. Whole exomic sequencing can
identify known and putative mutations in a patient's genome. The neurologist
must “think metabolic” in sorting out complex and difficult cases.
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From the manuscript
Because pediatricians, pediatric neurologists, or
pediatricians who specialize in genetics and metabolism usually see these
disorders, adult neurologists often do not include inherited metabolic diseases
in their differential diagnoses, except for those disorders that are well-known
to occur during adolescence or adulthood. When adults exhibit neurologic
features that are indicative of more common disorders, these individuals are
usually diagnosed with these disorders and subsequently treated as such. Not
until these therapies have failed to improve or resolve the symptoms, often
leaving the clinician perplexed, does the clinician turn to considering other
rare inherited metabolic or genetic disorders. However, over the last several decades,
an increasing number of adults are being diagnosed with inherited metabolic
diseases. This increase is due in part because of the technological advances in
metabolic diseases and genetics.
The clinician may perform some of the more common metabolic
disorder testing procedures, such as organic acids or acylcarnitine analysis,
resulting in the correct diagnosis. More recently, even newer technologies,
such as whole exomic sequencing (WES), have revealed the true diagnosis and led
the neurologist to the definitive diagnosis and appropriate treatment. WES
analysis is useful in identifying the underlying molecular basis of a genetic
disorder in an affected individual. Alterations in an individual's nucleotide
sequences are then compared to reference sequences of normal, control
individuals, thereby identifying mutations or variants that could possibly
explain the clinical findings in an affected individual. The increasing
recognition of inherited metabolic diseases in adults has been the subject of
new textbooks.
These principles specifically hit home with me in my studies
of the autosomal recessively inherited metabolic disorder biotinidase
deficiency, which I have been researching for the last 35 years. Biotinidase is
the enzyme that is required for recycling the vitamin biotin. Dietary free
biotin enters the cellular biotin pool via biotin transport. Once biotin is in
the cell, holocarboxylase synthetase attaches biotin to inactive apocarboxylases
(propionyl-CoA carboxylase, [beta]-methylcrotonyl-CoA carboxylase, pyruvate
carboxylase, and acetyl-CoA carboxylase), forming active holocarboxylases. The
holocarboxylases subsequently participate in amino acid catabolism, fatty acid
synthesis, and gluconeogenesis. Biotinidase releases biotin from biocytin or
proteolytically degraded holocarboxylases and biotin-bound dietary peptides.
The released biotin is recycled and enters the free biotin pool.
Biotinidase deficiency is the primary enzyme defect in most
individuals with late-onset multiple carboxylase deficiency. An individual with biotinidase deficiency
cannot recycle his or her endogenous biotin. The resultant secondary biotin
deficiency results in an inability to biotinylate the various apocarboxylases,
causing deficiencies of the various holocarboxylases. The multiple carboxylase
deficiencies result in the accumulation of toxic metabolites resulting in the
clinical symptoms. Supplementation with pharmacologic doses of exogenous biotin
circumvents the biotinidase deficiency and supplies the necessary free biotin
for the biotinylation of the carboxylases, thereby restoring normal holoenzyme
activities. Biotin supplementation is a lifelong therapy for these individuals.
Most clinicians have recognized biotinidase deficiency as a
childhood disease characterized by various neurologic symptoms, such as
lethargy, hypotonia, seizures, ataxia, and developmental delay, and cutaneous
features, such as eczematoid skin rashes, alopecia, and fungal infections. Symptoms markedly improve or resolve with
pharmacologic doses of the vitamin biotin. Because biotinidase deficiency meets the major
criteria for inclusion of a disorder in newborn screening, all the states in
the United States and many countries screen their newborns for the disorder. We have recently shown that continuous biotin
treatment prevents the development of symptoms in adolescents and adults with
the disorder.
We initially found several older children and young
adolescents with biotinidase deficiency, which we called delayed-onset
biotinidase deficiency, who presented with a spectrum of symptoms, including
paresis/paraplegia and scotomata, which is not usually seen in younger children
with the disorder.10 Over the last several years, a group of older adolescents
and adults has been identified with profound biotinidase deficiency who
exhibited symptoms of myelitis and spastic paresis/paraplegia with and without
retinal/visual abnormalities. In many of
these cases, because an inherited metabolic disorder, let alone biotinidase
deficiency, was not included in the differential diagnosis, many of these
individuals were thought to have multiple sclerosis, transverse myelitis,
myasthenia gravis, neuromyelitis optica, brainstem encephalitis, or Wernicke
encephalopathy. These individuals were treated with various regimens based on
these putative disorders, but failed to improve. Eventually these individuals
were diagnosed with biotinidase deficiency and treated with pharmacologic doses
of biotin. In most, symptoms improved or resolved with therapy. However, we
have recently shown that if the diagnosis and treatment are markedly delayed in
an adult, the symptoms can be irreversible. This exemplifies the importance of early
diagnosis and treatment to prevent irreversible damage.
Some metabolic disorders are screened for in newborns, but
not in all countries. However, even if a country currently screens its newborns
for various inherited metabolic disorders, there is a gap of time between when
the state or country began screening and the ages of the adult population that
may present with symptoms. In addition, even if an individual was found to be
unaffected by newborn screening, we must remember that newborn screening is, in
fact, screening, and is not always definitive at making or excluding a
diagnosis, especially when the screening is based on a cutoff value of a
specific metabolite. If a symptom or a constellation of symptoms suggests that
an individual may have a metabolic disorder, more specific testing is usually
warranted.
As we learn more about the natural history of adults with
metabolic diseases, we will gain more knowledge about the symptoms to be
included in a variety of differential diagnoses. Because the clinical spectrum
of symptoms may be misleading based on those disorders that usually present in
children or the symptoms are usually seen in other more common disorders,
neurologists will become more dependent on the newer technologies, but they
must be aware that the methodologies described above are available.
As stated above, many of the adults diagnosed with inherited
metabolic disorders were diagnosed because an astute clinician considered the
possibility of inherited metabolic disorder and performed the appropriate
metabolic testing. This is likely to change with an increasing awareness about
genetic testing methods, such as exomic sequencing. In fact, several of the
adults with biotinidase deficiency were not identified because the clinician
considered a metabolic disorder or specifically biotinidase deficiency, but
rather the clinician performed exomic sequencing, which subsequently identified
two nonallelic mutations in the biotinidase gene, indicating that the
individual had biotinidase deficiency. The definitive diagnosis was confirmed
by finding profoundly deficient serum biotinidase activity.
The take-home lessons for neurologists that I learned from
biotinidase deficiency that apply to many inherited metabolic disorders are as
follows:
1. The possibility of an inherited metabolic disorder should
be considered in adults with neurologic symptoms that may or may not mimic
those seen in affected children.
2. These inherited disorders must be included in the
differential diagnosis of adults who exhibit neurologic symptoms of a more
common disorder, but fail to improve with routine therapies.
3. Awareness of appropriate testing, such as organic acid
and amino acid analysis and exomic sequencing, can help to sort out these
disorders, thereby leading to appropriate diagnosis and treatment. Moreover,
exomic sequencing can identify specific alterations or mutations in an
individual's genome that identify a definitive diagnosis.
4. Neurologists should “think metabolic” in sorting out
their complex and difficult cases. If the neurologist is not comfortable with
these metabolic disorders, he or she should consider consulting or referring
such individuals to a geneticist or metabolic specialist.
Wolf B. Biotinidase deficiency should be considered in
individuals exhibiting myelopathy with or without vision loss. Mol Genet
Metabol 2015;116:113–118.
Girard B, Bonnemains C, Schmitt E, Raffo E, Bilbault C.
Biotinidase deficiency mimicking neuromyelitis optica beginning at the age of
4: a treatable disease. Mult Scler 2017;23:119–122.
Ferreira P, Chan A, Wolf B. Irreversibility of symptoms with
biotin therapy in an adult with profound biotinidase deficiency. J Inherit
Metab Dis Rep (in press 2017).
Demirturk Z, Senturk E, Kose A, Ozcan PE, Telci L. A case of
biotinidase deficiency in an adult with respiratory failure in the intensive
care unit. Balkan Med J 2016;33:563–565.
