Differentiating Familial Neuropathies from Guillain-Barré Syndrome

Differentiating Guillain-Barré syndrome (GBS) from inherited neuropathies and other acquired peripheral neuropathies requires understanding the atypical presentations of GBS and its variant forms, as well as historical and physical features suggestive of inherited neuropathies. GBS is typically characterized by the acute onset of ascending flaccid paralysis, areflexia, and dysesthesia secondary to peripheral nerve fiber demyelination. The disorder usually arises following a benign gastrointestinal or respiratory illness, is monophasic, reaches a nadir with several weeks, and responds to immunomodulatory therapy. Inherited neuropathies with onset before adulthood, whose presentation may mimic Guillain-Barré syndrome, are reviewed.

Key points

  • Guillain-Barré syndrome is the most common cause of acute flaccid paralysis in childhood. Acute inflammatory demyelinating polyneuropathy is the most common variant of Guillain-Barré syndrome and is diagnosed based on clinical presentation, as well as the presence of albuminocytologic dissociation in the cerebrospinal fluid and demyelinating changes on electromyography.

  • Numerous variants of Guillain-Barré exist and may mimic other causes of acquired peripheral neuropathy or inherited neuropathy.

  • Key to diagnosing a seemingly acquired peripheral neuropathy as an inherited neuropathy is recognizing subtle systemic manifestations, signs of long-standing neuromuscular disease, or a positive family history.

Introduction

The acute onset of flaccid limb weakness or sensory dysfunction in children and young adults prompts consideration of acquired peripheral neuropathies, the differential diagnosis of which includes Guillain-Barré syndrome (GBS), which is best conceptualized as a collection of clinically-related disorders characterized by peripheral nerve fiber dysfunction secondary to an acute inflammatory and presumed autoimmune mechanism. The most common form of GBS is acute inflammatory demyelinating polyradiculoneuropathy (AIDP), in which immune-mediated peripheral nerve fiber demyelination leads to weakness, areflexia, and paresthesia beginning in the distal extremities and progressing proximally. In addition to these distinctive findings, patients with AIDP variably experience autonomic dysfunction, neuropathic pain, voiding dysfunction, and progression of weakness to involve respiratory insufficiency and even failure. Diagnosis is contingent on recognizing the peripheral nerve as the source of the patient’s neuromuscular symptoms and subsequently undertaking an appropriate evaluation that shows the characteristic findings of albuminocytologic dissociation in the cerebrospinal fluid, peripheral nerve fiber demyelination on electromyography (EMG), and nerve root enhancement on MRI of the spine. The disorder typically develops within weeks of a benign gastrointestinal or respiratory illness, is monophasic, reaches a nadir within several weeks of symptom onset, and responds to immunomodulatory therapy, with many patients experiencing full recovery within several months of onset. However, up to 20% of patients with GBS are left with some degree of residual disability.

Although AIDP is the most common presentation of GBS in pediatrics, numerous variant forms have been described that differ with respect to immunologic target and symptom constellation. Variants such as Miller Fisher syndrome are characterized by prominent ophthalmoplegia, ataxia, and areflexia with absent weakness, whereas patients with the polyneuritis cranialis variant experience multiple cranial nerve palsies and severe peripheral sensory loss. Patients with axonal, rather than demyelinating, variants may lack sensory and autonomic symptoms but are at higher risk of respiratory failure. Diagnosis under these circumstances is more challenging, because these variant presentations may mimic other causes of acquired peripheral neuropathy. Furthermore, localization of the disorder to the peripheral nerve may be challenging when motor or sensory symptoms are subtle, multifocal, or seemingly not restricted to a readily identifiable peripheral nerve distribution. Despite these variations, the disorder still typically follows a monophasic course and responds to immunomodulation, with symptoms reaching a nadir within weeks and resolving within months.

The natural and treated history of GBS may at times confound certainty in the diagnosis. Up to 7% of patients with GBS experience recurrent attacks in the years following the initial event, despite receiving immunomodulatory therapy ; more acutely, up to 16% of patients with GBS experience treatment-related fluctuations, in which an initial improvement after treatment is followed by subsequent worsening of symptoms within the first 2 months of symptom onset. Furthermore, up to 5% of patients with presumed GBS ultimately meet diagnostic criteria for acute-onset chronic inflammatory demyelinating polyneuropathy (CIDP), with persistent or recurrent symptoms lasting longer than 2 months. In addition to recurrent episodes, treatment-related fluctuations, and acute-onset CIDP, the persistence of symptoms following immunomodulatory therapy should prompt consideration of an alternative cause of acute-onset acquired peripheral neuropathy, with a broad differential diagnosis that includes infectious, rheumatic, endocrinologic, toxic, nutritional, and other causes. Furthermore, in addition to chronic acquired conditions, the presence of atypical, persistent, or systemic symptoms should prompt consideration of inherited peripheral neuropathies. Many of these disorders develop insidiously and show systemic involvement that more overtly suggests an underlying genetic cause; however, some patients present with acute or subacute symptoms of peripheral neuropathy and subtle systemic symptoms. These presentations may mimic GBS, at least in initial presentation.

Patients with the acute onset of peripheral nervous system dysfunction are most likely to have an acquired cause of their disorder. Patients whose symptoms, physical findings, and diagnostic evaluation are consistent with GBS are often appropriately managed empirically with immunomodulatory therapy. Patients presenting atypically, either in terms of the timing of symptom development or with respect to symptom constellation, may have a variant of GBS, may have an alternative cause for their acquired peripheral neuropathy, or may have a rare and likely genetic cause for their symptoms. On occasion, patients with inherited peripheral neuropathies present acutely, although historical features and physical examination findings can reveal subtle signs of chronic, progressive nerve fiber dysfunction or systemic illness that indicate an underlying genetic cause for their symptoms.

Introduction

The acute onset of flaccid limb weakness or sensory dysfunction in children and young adults prompts consideration of acquired peripheral neuropathies, the differential diagnosis of which includes Guillain-Barré syndrome (GBS), which is best conceptualized as a collection of clinically-related disorders characterized by peripheral nerve fiber dysfunction secondary to an acute inflammatory and presumed autoimmune mechanism. The most common form of GBS is acute inflammatory demyelinating polyradiculoneuropathy (AIDP), in which immune-mediated peripheral nerve fiber demyelination leads to weakness, areflexia, and paresthesia beginning in the distal extremities and progressing proximally. In addition to these distinctive findings, patients with AIDP variably experience autonomic dysfunction, neuropathic pain, voiding dysfunction, and progression of weakness to involve respiratory insufficiency and even failure. Diagnosis is contingent on recognizing the peripheral nerve as the source of the patient’s neuromuscular symptoms and subsequently undertaking an appropriate evaluation that shows the characteristic findings of albuminocytologic dissociation in the cerebrospinal fluid, peripheral nerve fiber demyelination on electromyography (EMG), and nerve root enhancement on MRI of the spine. The disorder typically develops within weeks of a benign gastrointestinal or respiratory illness, is monophasic, reaches a nadir within several weeks of symptom onset, and responds to immunomodulatory therapy, with many patients experiencing full recovery within several months of onset. However, up to 20% of patients with GBS are left with some degree of residual disability.

Although AIDP is the most common presentation of GBS in pediatrics, numerous variant forms have been described that differ with respect to immunologic target and symptom constellation. Variants such as Miller Fisher syndrome are characterized by prominent ophthalmoplegia, ataxia, and areflexia with absent weakness, whereas patients with the polyneuritis cranialis variant experience multiple cranial nerve palsies and severe peripheral sensory loss. Patients with axonal, rather than demyelinating, variants may lack sensory and autonomic symptoms but are at higher risk of respiratory failure. Diagnosis under these circumstances is more challenging, because these variant presentations may mimic other causes of acquired peripheral neuropathy. Furthermore, localization of the disorder to the peripheral nerve may be challenging when motor or sensory symptoms are subtle, multifocal, or seemingly not restricted to a readily identifiable peripheral nerve distribution. Despite these variations, the disorder still typically follows a monophasic course and responds to immunomodulation, with symptoms reaching a nadir within weeks and resolving within months.

The natural and treated history of GBS may at times confound certainty in the diagnosis. Up to 7% of patients with GBS experience recurrent attacks in the years following the initial event, despite receiving immunomodulatory therapy ; more acutely, up to 16% of patients with GBS experience treatment-related fluctuations, in which an initial improvement after treatment is followed by subsequent worsening of symptoms within the first 2 months of symptom onset. Furthermore, up to 5% of patients with presumed GBS ultimately meet diagnostic criteria for acute-onset chronic inflammatory demyelinating polyneuropathy (CIDP), with persistent or recurrent symptoms lasting longer than 2 months. In addition to recurrent episodes, treatment-related fluctuations, and acute-onset CIDP, the persistence of symptoms following immunomodulatory therapy should prompt consideration of an alternative cause of acute-onset acquired peripheral neuropathy, with a broad differential diagnosis that includes infectious, rheumatic, endocrinologic, toxic, nutritional, and other causes. Furthermore, in addition to chronic acquired conditions, the presence of atypical, persistent, or systemic symptoms should prompt consideration of inherited peripheral neuropathies. Many of these disorders develop insidiously and show systemic involvement that more overtly suggests an underlying genetic cause; however, some patients present with acute or subacute symptoms of peripheral neuropathy and subtle systemic symptoms. These presentations may mimic GBS, at least in initial presentation.

Patients with the acute onset of peripheral nervous system dysfunction are most likely to have an acquired cause of their disorder. Patients whose symptoms, physical findings, and diagnostic evaluation are consistent with GBS are often appropriately managed empirically with immunomodulatory therapy. Patients presenting atypically, either in terms of the timing of symptom development or with respect to symptom constellation, may have a variant of GBS, may have an alternative cause for their acquired peripheral neuropathy, or may have a rare and likely genetic cause for their symptoms. On occasion, patients with inherited peripheral neuropathies present acutely, although historical features and physical examination findings can reveal subtle signs of chronic, progressive nerve fiber dysfunction or systemic illness that indicate an underlying genetic cause for their symptoms.

Acute inflammatory demyelinating polyradiculoneuropathy and the differential diagnosis of acquired peripheral neuropathy

The annual incidence of GBS in pediatrics is as high as 1.34 cases per 100,000 in individuals less than 15 years of age, with a slight male predominance. Up to two-thirds of cases are preceded by a mild respiratory or gastrointestinal illness in the weeks before the onset of symptoms, with typical infections including Campylobacter jejuni enteritis and cytomegalovirus. Acute inflammatory demyelinating polyradiculoneuropathy accounts for approximately 90% of cases of GBS in North America. The typical presentation of AIDP is of a person who complains of numbness or tingling in the legs and feet before developing progressive clumsiness and weakness that seems to ascend symmetrically up the legs over a matter of several days. In children, this may be mistaken for fatigue, growing pains, joint problems, or clumsiness caused by illness. Symptoms generally peak within 2 to 4 weeks of onset, and as the disease progresses, the patient develops an ascending flaccid paralysis with areflexia that may affect the hands, cranial nerves, and ultimately the diaphragm, which may lead to respiratory failure. Most patients develop gait unsteadiness or an inability to ambulate and most complain of neuropathic pain, whereas approximately half have bulbar symptoms and half show autonomic dysfunction. The most common manifestation of autonomic dysfunction is sinus tachycardia, although additional manifestations may include bradycardia, blood pressure lability, and less commonly urinary retention or gastrointestinal symptoms.

Timely and appropriate diagnosis requires recognizing the peripheral nerve as the source of the patient’s symptoms and differentiating peripheral neuropathy from myelopathy, myopathy, or lesions in the brain. Key historical features and physical examination findings suggestive of peripheral nerve fiber dysfunction include a distal-to-proximal progression of symptoms and findings, because both demyelinating and axonal disorders affect the peripheral nerves in a length-dependent fashion. Sensory symptoms tend to predominate early in the course of illness, although they may be vague at first, consisting of numbness and tingling in a stocking-glove distribution. As paresthesia and pain progress proximally, flaccid weakness and diminished or absent tendon reflexes develop. Severe sensory involvement may lead to sensory ataxia, wherein a loss of proprioceptive input and joint position sensation leads to clumsiness and poor coordination when the patient closes the eyes and eliminates visual feedback from the regulation of movement. Differentiating sensory ataxia from weakness requires performing movements in a plane of motion that does not require resistance against gravity. The symptoms of peripheral neuropathy in AIDP tend to be symmetric and progress in an ascending fashion, and although some variations in this presentation are possible, major deviations from this pattern, such as unilateral findings or proximal-to-distal progression, should prompt consideration of alternative causes. Hyperreflexia, spasticity, and cerebellar ataxia indicate central, rather than peripheral, involvement, and specifically indicate intracranial or upper motor neuron disorders. Proximal weakness tends to predominate rather than distal weakness in myopathies, and myelopathies tend to present with sensory levels or dermatomally-distributed symptoms.

With the peripheral nerve fiber identified as the source of the patient’s symptoms, the typical evaluation for suspected GBS includes lumbar puncture and an electromyogram. MRI of the brain or spine may be indicated if there are concerns about intracranial disorders or if the speed of symptom progression or distribution of symptoms suggests disorder in the spinal cord, as opposed to the peripheral nerve. Albuminocytologic dissociation, in which the cerebrospinal fluid protein level is increased but the total nucleated cell count remains within normal limits, is somewhat specific for GBS but is fairly insensitive, being present in up to half of affected patients in the first week of illness and up to 75% of affected patients by the third week of illness. Patients who have a history of infection with human immunodeficiency virus may show cerebrospinal fluid pleocytosis in the context of GBS; otherwise, the presence of pleocytosis suggests an alternative diagnosis. Contrast-enhanced MRI of the spine may show enhancement of the nerve roots and cauda equina, a finding which has a sensitivity greater than 90% for GBS but which is fairly nonspecific.

EMG may distinguish whether a neuropathic process is demyelinating, axonal, or a combination of both, and nerve conduction velocity studies should be performed on at least 2 nerves to confirm findings. The critical measures are the amplitude of the compound motor action potential (CMAP) at a proximal and distal site, the conduction velocity along the tested nerve, and the qualities of the F-wave. Demyelinating processes show the following 4 characteristic changes on EMG: (1) reduced maximum motor conduction velocity and (2) partial conduction block or abnormal temporal dispersion leading to (3) prolonged motor distal latency and (4) prolonged or absent F-wave latencies. A reduction of conduction velocity by 30%, an increase in temporal dispersion by 30%, and a distal CMAP and F-wave latency of 150% of normal limits has a sensitivity of 72% for detecting AIDP. However, in demyelinating diseases such as AIDP, some patients have normal responses early in the disease course and an EMG should be repeated in those patients after 1 to 2 weeks for maximum diagnostic yield if there is ongoing uncertainty in the diagnosis. The reported order in which abnormalities appear is absence or decrease in the tibial H-wave, dispersion of the F-wave, abnormal CMAP dispersion, prolonged CMAP and F-wave latencies, and then decrease in CMAP conduction velocity. In axonal disorders, the EMG reveals normal conduction velocities but decreased distal CMAP amplitudes; sensory nerve action potential amplitudes may be normal or decreased depending on the presence of sensory symptoms.

Patients whose presentation and evaluation are consistent with AIDP receive supportive care and undergo treatment targeted at curbing the aberrant immunologic response presumed to be driving the peripheral nerve fiber dysfunction. Intravenous immunoglobulin is the treatment modality of choice in pediatrics, although plasmapheresis may be used. In general, AIDP is a monophasic illness with a good prognosis. However, up to 20% of patients with GBS require assisted ventilation for respiratory insufficiency or failure, and mortality approaches 4%, either from respiratory or autonomic causes.

Patients whose history, physical examination findings, or results of diagnostic evaluation are inconsistent with AIDP may have a variant of GBS or may have an alternative cause of acquired peripheral neuropathy. The differential diagnosis of acquired peripheral neuropathy in pediatrics is presented in Box 1 .

Box 1

  • Infectious

  • Chronic Chagas disease

  • Diphtheria

  • Human immunodeficiency virus

  • Leprosy

  • Lyme disease

  • Rabies

  • West Nile virus a

  • Noninfectious inflammatory

  • Celiac disease

  • CIDP

  • GBS

  • Eosinophilic granulomatosis with polyangiitis

  • Henoch-Schönlein purpura a

  • Inflammatory bowel disease a

  • Juvenile idiopathic arthritis a

  • Polyarteritis nodosa

  • Sarcoidosis

  • Sjögren syndrome

  • Systemic lupus erythematosus

  • Granulomatosis with polyangiitis

  • Endocrine

  • Diabetes mellitus

  • Hypothyroidism

  • Medications

  • Bortezomib

  • Chloramphenicol

  • Cisplatin

  • Cytarabine

  • Isoniazid

  • Lamivudine

  • Metronidazole

  • Paclitaxel

  • Penicillin

  • Phenytoin

  • Stavudine

  • Sulfonamides

  • Thalidomide

  • Vincristine

  • Zidovudine

  • Nutritional

  • Vitamin B 1 (thiamine) deficiency

  • Vitamin B 2 (riboflavin) deficiency

  • Vitamin B 6 (pyridoxine) deficiency or toxicity

  • Vitamin B 12 (cobalamin) deficiency

  • Vitamin E (tocopherol) deficiency

  • Other

  • Critical illness polyneuropathy/myopathy

  • Bone marrow transplant–related graft-versus-host disease

  • Lymphoma a

  • Neurofibromatosis

  • Porphyria

  • Traumatic neuropathy

  • Uremia

  • Toxic

  • Arsenic

  • Gold

  • Lead

  • Mercury

  • N-hexane (glue huffing)

  • Organophosphates

  • Thallium

a Rare manifestation.

Causes of pediatric-onset acquired peripheral neuropathy

Variant presentations of Guillain-Barré syndrome

Variant presentations of GBS, their clinical distinctions from AIDP, and pertinent diagnostic findings are presented in Table 1 . Atypical presentations, particularly in those variants involving the cranial nerves or lacking prominent sensory findings, may make localization to the peripheral nerve challenging. However, most variants can be categorized based on the primary symptom constellation: those variants that present with ophthalmoplegia, ataxia, and areflexia without limb weakness; or those that present with plegia or paresis with variable sensory and autonomic symptoms.

Table 1
Variant forms of Guillain-Barré syndrome in pediatrics. Clinical features that distinguish from acute inflammatory demyelinating polyradiculoneuropathy and key diagnostic features, including antiganglioside antibody profiles
Variant Clinical Distinctions from AIDP Diagnostic Features
Ophthalmoplegia-Ataxia-Areflexia Constellation
Miller Fisher syndrome Ophthalmoplegia, ataxia out of proportion to sensory loss, absent weakness EMG/NCV studies showing axonopathy, although some patients may have demyelinating features, also with reduced or absent sensory nerve action potentials; antibodies isolated include anti-GT 1a , GQ 1b, GD 1b
Bickerstaff brainstem encephalitis Considered a subtype of Miller Fisher syndrome; includes ophthalmoplegia, ataxia, encephalopathy, and hyperreflexia EMG/NCV studies similar to Miller Fisher; MRI findings variable but may include hyperintense foci in the brainstem on T2-weighted imaging, thalamic or cerebellar lesions possible; antibodies isolated include anti-GT 1a , GQ 1b, GD 1b
Plegia/Paresis With or Without Sensory and Autonomic Symptoms Constellation
Paraparetic GBS Weakness and paresthesia restricted to the lower extremities EMG/NCV studies similar to AIDP
Facial diplegia and distal limb paresthesia Similar to AIDP but with bifacial weakness; rare in children but may present in adolescents EMG/NCV studies similar to AIDP; antibodies isolated include anti-GM 2 ; association with cytomegalovirus infection
Polyneuritis cranialis Multiple bilateral cranial nerve palsies (often sparing the optic nerve); severe peripheral sensory loss MRI showing enhancement of cranial nerves; antibodies isolated include anti-GQ 1 , GT 1
Pharyngeal-cervical-brachial weakness Swallowing dysfunction; weakness of oropharyngeal, neck, and shoulder muscles EMG/NCV studies showing axonopathy; antibodies isolated include anti-GT 1a , GQ 1b , GD 1a
Acute motor axonal neuropathy Absence of sensory or autonomic symptoms; rapid progression of ascending symmetric weakness; higher likelihood of respiratory failure EMG/NCV studies showing motor axonopathy without demyelinating features; antibodies isolated include anti-GM 1 , GM 1b , GD 1a , GalNac-GD 1a ; strong association with C jejuni infection
Acute motor-sensory axonal neuropathy Absence of autonomic symptoms; prolonged course with possible muscle wasting; rare in children EMG/NCV studies showing motor and sensory axonopathy without demyelinating features; antibodies isolated include anti-GM 1 , GM 1b , GD 1a ; strong association with C jejuni infection
Pure sensory GBS Significant sensory ataxia with absent reflexes and minor motor involvement EMG/NCV studies with demyelinating features; antibodies isolated include anti-GD 1b
Abbreviation: NCV, nerve conduction velocity.

Miller Fisher syndrome is the prototypical variant of the ophthalmoplegia-ataxia-areflexia constellation and accounts for up to 10% of GBS cases in Western countries, although in certain eastern Asian populations it accounts for up to 25% of cases of GBS. Up to 10% of patients with Miller Fisher syndrome have additional findings of encephalopathy and hyperreflexia consistent with Bickerstaff brainstem encephalitis. Some patients in this spectrum may lack ataxia or ophthalmoplegia, and some have symptoms that overlap with the plegia-paresis constellation and include features of both constellations.

Symptomatically, patients in the plegia-paresis constellation often seem to have findings similar to AIDP, although with incomplete anatomic distributions or variability in the degree or completeness of sensory, motor, and autonomic findings. For example, patients with paraparetic GBS have findings restricted to the lower extremities, whereas patients with pharyngeal-cervical-brachial GBS have weakness in a capelike distribution that also includes the pharyngeal musculature, leading to swallowing dysfunction. Patients with acute motor axonal neuropathy lack sensory and autonomic symptoms, whereas patients with sensory GBS have minimal, if any, weakness.

Neurophysiologically, there is variability both within and between the ophthalmoplegia-ataxia-areflexia constellation and the plegia-paresis constellation with respect to underlying disorder, with some variants showing a demyelinating pattern and others showing an axonal pattern. Although the specific immunologic target in AIDP is not known, specific antiganglioside antibodies have been identified for many GBS variants. The formation of antiganglioside antibodies is thought to underlie the immune-mediated axonopathy seen in axonal variants, and the distribution of particular gangliosides throughout the peripheral nervous system is thought to underlie the variability in the distribution of symptoms. Although these immunohistologic distinctions provide valuable information regarding the pathophysiology of GBS, distinguishing variants of GBS by symptom constellation may ultimately prove more valuable in the immediate clinical evaluation period. It is further worth noting that diagnosis of these variants is based on clinical grounds and the results of neuroimaging and neurophysiologic investigations and does not require demonstration of antiganglioside antibodies, which may not be widely available for testing in clinical settings or which may require significant time to complete and lead to delays in therapy.

Patients who lack an infectious prodrome and whose symptoms persist beyond 2 months may have acute-onset CIDP, as opposed to GBS. Treatment of CIDP is still designed to curb aberrant immunologic activity via immunomodulation, although many patients experience chronic, stable symptoms, or have a prolonged relapsing-remitting course. Alternatively, patients with more chronic or persistent symptoms, or whose history and physical examination reveal systemic involvement or more long-standing neurologic dysfunction, may have an inherited peripheral neuropathy.

Inherited peripheral neuropathies that may mimic Guillain-Barré syndrome

The variability and overlap in symptoms among the variants of GBS open the possibility of misdiagnosis, including diagnosing an inherited neuropathy as an acquired one. Some inherited neuropathies can mimic GBS, particularly in the initial presentation of neuropathic findings, although most show a chronically progressive course or involve multiple organ systems in a manner that ultimately suggests the underlying genetic nature of the disorder. Diagnosis becomes challenging when systemic manifestations are subtle, lacking, or temporally remote from the appearance of neuropathic findings, or when the disorder follows a relapsing-remitting or episodic course. In addition to evaluating for systemic signs and symptoms, key to determining whether an apparent case of atypical GBS may be caused by an inherited neuropathy is looking for subtle signs of long-standing motor, sensory, or autonomic neuropathy, such as weakness or gait abnormalities when asymptomatic, muscular atrophy in the affected limbs that is out of proportion to the duration of symptoms, or limb deformities secondary to neuromuscular weakness. Other features suggestive of inherited disorders include dysmorphic features or a family history of consanguinity.

Hereditary peripheral neuropathies are a heterogeneous group of disorders classified by type of neurons involved (sensory, motor, autonomic, or a combination), primary pattern of involvement (proximal or distal), and type of neuronal injury (demyelinating or axonal). Some have a relapsing-remitting or episodic course. An episodic nature to the disease or an apparent response to immunomodulation, often pursued when initial diagnostic impressions favor GBS, may suggest against an inherited disorder but does not adequately exclude a genetic mechanism, because intercurrent illnesses may unmask or worsen an underlying inherited disorder, particularly a mitochondrial disorder. Furthermore, positive sensory symptoms, such as paresthesia, may not be evident, and therefore the lack of such symptoms between episodes does not exclude the possibility of subtle but progressive sensory nerve dysfunction between episodes.

Similarly, some patients may show systemic manifestations long before or after the development of peripheral nerve disease, and this separation in time may make it challenging to recognize distinct findings as a part of the same underlying disease process. The authors evaluated a 19-year-old male patient who was admitted to our hospital for respiratory insufficiency secondary to severe neuromuscular weakness. His history before presenting to our institution was notable for an acute-onset and seemingly idiopathic restrictive cardiomyopathy at 8 years of age that required orthotopic heart transplant. At the time of transplant, he otherwise had no evidence of neuromuscular or systemic disease, and following transplant was stable on an antirejection medication regimen until age 12 years, when he developed a slowly progressive sensorimotor polyneuropathy heralded by episodes of severe lower extremity paresthesia and pain. EMG at that time showed a mixed axonal and demyelinating polyneuropathy. Over the next several years he developed signs of progressive neuromuscular disease, with foot deformities, scoliosis, and profound muscular atrophy. Whole-exome sequencing at 19 years of age revealed a mutation in BAG3 consistent with myofibrillar myopathy, and review of preserved specimen slides from his diseased heart showed changes suggestive of myofibrillar myopathy as well. Although the course of his neuropathy was more indolent and chronically progressive, some patients manifest with acute-onset peripheral neuropathy and either subtle or temporally remote systemic signs and symptoms that may make the recognition of an inherited disorder challenging.

Genetic disorders associated with pediatric-onset peripheral neuropathy are listed in Table 2 . These disorders can be broadly categorized as being part of the Charcot-Marie-Tooth or hereditary motor-sensory neuropathy spectrum and related disorders, as being secondary to mitochondrial disease, or as having a distinct genetically determined pathophysiology that interrupts peripheral nerve fiber function.

Oct 2, 2017 | Posted by in PEDIATRICS | Comments Off on Differentiating Familial Neuropathies from Guillain-Barré Syndrome

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